As previously discussed, pursuant to a consent decree, FDA was to finalize the over-the-counter (OTC) topical health care antiseptic drug products monograph with respect to triclosan by January 15, 2018. Rather than limiting the rulemaking to the single active ingredient, triclosan, FDA took it upon itself to finalize the monograph for all OTC health care antiseptic active ingredients.

Ahead of time, on Dec. 20, 2017, FDA issued what it identifies as the final rule for health care antiseptics.  Upon further reading, it turns out that FDA is not yet done, however.  The final rule constitutes a final determination that 24 active ingredients are not generally recognized as safe and effective (GRASE); they are added to the list of unapproved new drugs in 21 C.F.R. § 310.545.  The compliance (or effective) date is Dec. 20, 2018.  On or after that date, any OTC health care antiseptic drug product that contains any of these 24 active ingredients cannot legally be introduced into interstate commerce unless it is the subject of an FDA-approved New Drug Application (NDA).

As we reported earlier this year, in February 2017, FDA deferred action on six active ingredients (benzalkonium chloride, benzethonium chloride, chloroxylenol, alcohol, isopropyl alcohol and povidone-iodine) pending additional data. Thus, the rule making on health care antiseptic drug products remains incomplete.  FDA has not set a specific deadline for final action on these ingredients but instead with address their monograph (GRASE) status “either after completion and analysis of ongoing studies to address the safety and effectiveness data gaps . . . or at a later date, if these studies are not completed.”

In addition to finding the 24 active ingredients non-GRASE, FDA determined that chlorhexidine is not eligible for evaluation under the OTC drug review process because this ingredient was not included in any health care antiseptic product marketed before May 1972. Thus, any chlorhexidine-containing health care antiseptic may be marketed only if approved by FDA.  FDA also has determined that alcohol for use as a surgical hand scrub and benzethonium chloride for use as a health care personnel hand rub and surgical hand rub are ineligible for the OTC drug review for lack of evidence that products containing these ingredients were marketed before May 1972.

The preamble to the final rule discusses FDA’s responses to comments about the new efficacy testing requirements for the various types of health care antiseptics. These testing requirements apply to the six active ingredients for which action has been deferred and will not come as a surprise to the companies working on the collection of data for these ingredients.  The final rule does not address testing of final formulations because, at this time, FDA has not found any of the active ingredients GRASE.  Thus, rule making for testing of final products would be premature.

FDA stresses that the final rule does not cover

• Consumer antiseptic washes
• Consumer antiseptic rubs
• First aid antiseptics
• Antiseptics used by the food industry

Rules for these product categories are in various stages of completion.   FDA must issue a final rule for consumer antiseptic rubs by April 15, 2019. No deadline has been set for completion of the rule making regarding first aid antiseptics and antiseptics used by the food industry because those categories of products were not included in the consent decree.

Obscured last week amidst the tumultuous passage of tax reform, Congress urged the Drug Enforcement Administration (“DEA”) in a bipartisan letter to quickly update its regulations and guidance on the partial filling of schedule II controlled substance prescriptions. The letter notes that “[l]arge amounts of unused medications are a key contributor” to the nationwide opioid crisis and that between 67% and 92% of surgery patients “reported they had unused opioids remaining after the procedures.”  Letter from Congress of the United States, to Robert Patterson, Acting Administrator, DEA (Dec. 21, 2017).

The letter states that Congress passed the Comprehensive Addiction and Recovery Act (“CARA”) in July 2016 in part to prevent further stockpiling of unused prescribed opioids by amending the Controlled Substances Act (“CSA”) to enable patients or physicians to request that pharmacists partially fill schedule II substances that include prescription opioids and to allow remaining quantities to be filled up to 30 days after issuance of a prescription if necessary.

Prior law and current DEA regulations allow pharmacists to partially fill schedule II controlled substance prescriptions only if the pharmacy is unable to dispense the full prescribed quantity. 21 C.F.R. § 1306.13(a).  Pharmacists may dispense the remaining quantity within 72 hours of the first partial dispensing and cannot dispense any further prescribed quantity beyond 72 hours thereby requiring the prescriber to issue a new prescription.  21 C.F.R. § 1306.13(a).  Current regulations also allow partial dispensing of schedule II prescriptions to patients in a Long Term Care Facility or those diagnosed with a documented terminal illness.  21 C.F.R. § 1306.13(b).  Pharmacists can partially fill schedule III-V controlled substance prescriptions as long as no dispensing occurs after six months from the date of issue.  21 C.F.R. § 1306.23.

CARA amended the CSA to allow for the partial dispensing of a schedule II prescription if not prohibited by state law, requested by the patient or prescriber and the total quantity dispensed in partial fillings does not exceed the total quantity prescribed. 21 U.S.C. § 829(f)(1).  The amended CSA prohibits further partial dispensings later than 30 days after the prescription is written and no later than 72 hours in emergency situations.  21 U.S.C. § 829(f)(2).  The letter urges DEA to “swiftly” update its regulation and guidance as pharmacists and prescribers, “critical partners in the fight against the opioid epidemic,” are reluctant to comply with the amended CSA’s partial dispensing provisions until the agency does so.

The U.S. Court of Appeals for the Second Circuit issued a decision a couple of weeks ago reversing the conspiracy conviction of a defendant for distribution of unapproved drugs, among other things.  The trial court had rejected evidence relating to an advice-of-counsel defense asserted by the defendant.  The Second Circuit’s decision is important to the issue of the advice of counsel in connection with regulatory decisions.

A summary of the factual background included in the appellate decision follows:

• Mr. Scully was one of the founders of “Pharmalogical, Inc.,” named either pursuant to a dastardly misspelling of “pharmacological” or as a clever marketing device.
• The company registered with New York State authorities as a wholesale distributor of pharmaceutical products.
• Mr. Scully managed the day-to-day operations of the company, which imported European or Canadian versions of FDA-approved drugs and medical devices at prices substantially below what the products are available for in the United States, and resold the products to customers in the United States.
• Mr. Scully sought and received from a lawyer a letter that the Second Circuit found led Mr. Scully to believe he was authorized to import and sell the products. The opinion said, according to the Second Circuit, that Pharmalogical had not received any notification from FDA that it was operating in violation of the Federal Food, Drug, and Cosmetic Act, and that Pharmalogical had “no reason to believe it was not operating in compliance” with that statute.
• If Mr. Scully, the lawyer, the trial judge, or members of the Second Circuit panel deciding the case were regular and longstanding readers of this blog, they may have remembered that FDA has steadfastly asserted that the importation of prescription drugs into the United States is illegal, either because the drugs are drugs that are reimported into the United States, or because they are unapproved new drugs, or because they lack adequate directions for use (see our previous posts here, here, and here).
• Mr. Scully used the letter to convince customers that it was legal for him to wholesale Botox (a prescription drug).
• Mr. Scully then decided to branch into the importation from Europe of Mirena intrauterine contraceptive devices (medical devices), which he wholesaled in the United States without registering as being the initial importer of those devices. He secured a similar letter from the same lawyer asserting that “the importation of Mirena . . . from Finland into the United States by Pharmalogical, Inc. for resale to the end user, would not violate the criminal laws of the United States.”
• Mr. Scully then branched into the importation of oncology products, according to the Second Circuit.

At trial, the lawyer who provided the advice discussed above testified and was cross-examined. Following traditional prosecutorial tactics, the government established the Mr. Scully had not shared pertinent information with the attorney, including that he advertised products as being FDA-approved when they were not, and that U.S. customs officials had seized some of the drugs Mr. Scully attempted to import because they had foreign-language labeling that was not consistent with FDA-approved versions of the drugs.

Mr. Scully’s attorney also attempted to introduce evidence from Mr. Scully’s testimony that a second lawyer had also told Mr. Scully that Mr. Scully’s conduct was not illegal (the lawyer did not call that lawyer as a witness). The trial judge refused, at first, to allow hearsay testimony from Mr. Scully about the second lawyer’s opinion.  Then, the trial judge reconsidered, conceding that the defense lawyer was correct that the evidence was not inadmissible as hearsay (it was not offered for the truth of the matter asserted), but ruled the testimony was inadmissible because it was unduly prejudicial.

Mr. Scully was convicted by a jury after a five-week trial on several counts of mail and wire fraud, conspiracy to defraud the federal government, illegal distribution of unapproved drugs, unregistered wholesale distribution of drugs, and distribution of misbranded drugs. He was sentenced to 60 months in prison.

Mr. Scully then argued to the Second Circuit that the second lawyer’s opinion was important, and should not have been excluded. The Second Circuit agreed.

The Second Circuit went on to discuss the jury instruction delivered by the trial judge, saying it inappropriately placed the burden on the defendant to prove advice of counsel. The Second Circuit panel reiterated the standards set forth by its predecessor in United States v. Beech-Nut Nutrition Corp., 871 F.2d 1181 (2d Cir. 1989), a decision on a criminal trial handled by John Fleder, one of our esteemed Senior Counsel, when he worked for the Department of Justice.  The discussion is informative and interesting for those who are concerned about clients’ reliance on attorney advice, in our field.  But you can read the decision, or read Beech-Nut, or call John, because the length of this blog post already exceeds the extent of concentration appropriate for a blog post.  Mindful of that, we are still persuaded by John to add the following points.  In industries closely regulated by FDA, companies and individuals can get important protection from abusive criminal prosecutions by establishing that their actions were taken in good-faith reliance on advice given by legal counsel, as long as:

(1)       That advice is rendered by a lawyer, not a non-lawyer consultant;

(2)       The client discloses all material facts to the lawyer before the client undertakes the activity in question, rather than afterwards; and

(3)       The advice is legal advice, not business advice.

John also suggests making a contemporaneous record that the client has disclosed all material facts to the lawyer before acting and that the lawyer in good faith tells the client that the proposed conduct is legal. Even if the lawyer’s advice is not legally correct or is inconsistent with how FDA construes the relevant law, the defense should still be available.  But a court is more likely to conclude the advice was sought and rendered in good faith if the client solicits the advice from a recognized expert in the field.

Mr. Scully will get a new trial, unless the government settles or decides not to pursue a second trial.

In 2007, Congress determined that the public health would be adequately protected if manufacturers and importers of lower risk class I and II medical devices provided summary quarterly reporting of malfunctions to FDA. This system would replace the more burdensome approach of requiring individual 30‑day Medical Device Reports (MDRs) for each device malfunction. At the same time, FDA was granted authority to create exceptions by publishing lists in the Federal Register of class I and II devices that would continue providing individual 30‑day malfunction reports. FDA also was granted authority to create exceptions for specific devices by the simple expedient of sending a letter to the manufacturer or importer.

As amended in 2007, here is what Section 519 of the Federal Food, Drug, and Cosmetic Act statute now says about malfunction reporting:

Records and reports on devices

(a) General rule

Every person who is a manufacturer … of a device intended for human use shall establish and maintain such records, make such reports, and provide such information, as the Secretary may by regulation reasonably require to assure that such device is not adulterated or misbranded and to otherwise assure its safety and effectiveness. Regulations prescribed under the preceding sentence—

(1) shall require a device manufacturer or importer to report to the Secretary whenever the manufacturer or importer receives or otherwise becomes aware of information that reasonably suggests that one of its marketed devices—

*   *   *

(B) has malfunctioned and that such device or a similar device marketed by the manufacturer or importer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur, which report under this subparagraph—

(i) shall be submitted in accordance with part 803 of title 21, Code of Federal Regulations (or successor regulations), unless the Secretary grants an exemption or variance from, or an alternative to, a requirement under such regulations pursuant to section 803.19 of such part, if the device involved is—

(I) a class III device;

(II) a class II device that is permanently implantable, is life supporting, or is life sustaining; or

(III) a type of device which the Secretary has, by notice published in the Federal Register or letter to the person who is the manufacturer or importer of the device, indicated should be subject to such part 803 in order to protect the public health;

(ii) shall, if the device is not subject to clause (i), be submitted in accordance with criteria established by [FDA] for reports made pursuant to this clause, which criteria shall require the reports to be in summary form and made on a quarterly basis ….

In short, the law today is that devices are subject only to summary quarterly reporting of malfunctions, unless they are in class III, in class II but permanently implantable, life supporting or life sustaining, or excepted from quarterly reporting by FDA in a Federal Register notice or by direct letter.

For unexplained reasons, FDA refuses to implement the statute. We wrote about it in detail five years ago.

Now FDA has announced in the Federal Register a “proposed program for manufacturer reporting of certain device malfunction medical device reports (MDRs) in summary form.” 82 Fed. Reg. 60922, 60922 (Dec. 26, 2017). This proposed program “reflects FDA’s findings from a pilot program the Agency conducted to study summary reporting formats for malfunction MDRs.” Id.

FDA acknowledges the 2007 statutory requirement now embodied in Section 519 of the FDCA. 82 Fed. Reg. at 60923. It also acknowledges the benefits of summary reporting for lower risk devices. Id. at 60924. Specifically:

The pilot demonstrated several important findings. First, participants were able to reduce the volume of reports by over 87 percent using the pilot format, while preserving the essential information regarding the context around malfunction events. This increased efficiency in reporting and in the Agency review and processing of malfunction reports. The format also allowed for simple, transparent, and cost-effective reporting through existing electronic reporting processes for submission of electronic MDRs (eMDRs) to FDA, in accordance with the Medical Device Reporting: Electronic Submissions Requirements Final Rule (eMDR Final Rule) published in the Federal Register of February 14, 2014 (79 FR 8832). Based upon observations from the pilot experience, this summary format was usable for both large and small firms with varying numbers of marketed devices. Lastly, summary reports collected in this format could be more easily shared publicly, facilitating transparency of malfunction reporting.

Consistent with these findings, FDA believes that bundling “like events” together into a single summary report description would have benefits for manufacturers, FDA, and the public. For many manufacturers, this approach would greatly reduce the volume of reports that they would need to submit to FDA. For FDA, information would be received in a streamlined manner that would facilitate more efficient understanding of malfunction issues. For the public, summary reports could make malfunction event trends for a particular device more readily transparent. [Id. at 60923‑24.]

Yet, despite this acknowledgment, FDA refuses to follow the law. In the notice, FDA specifically clarifies that this proposed program does not implement the 2007 statute. 82 Fed. Reg. at 60923. FDA casts the proposed program as a voluntary opt-in program pursuant to its regulatory authority to grant MDR exemptions, variances, and/or waivers under 21 C.F.R. § 803.19. Id. at 60924.

The motive for the proposed program is apparently to fulfill certain goals agreed to between FDA and industry in a commitment letter submitted to Congress and referenced in the Medical Device User Fee Amendments Act of 2017. Id. at 60922. It is left unexplained how this commitment letter could override the statute enacted in 2007 and codified in Section 519 of the FDCA.

Indeed, the proposed program actually inverts the statute. As quoted above, Congress directed FDA that all class I and II devices are subject to summary quarterly reporting of malfunctions, unless FDA specifically excepts them in a Federal Register notice or by letter. Under the proposed program, in contrast, FDA will list the eligible product codes and allow manufacturers of products within such codes to opt‑in if certain conditions do not apply. Id. at 60924‑25.

Not to put too fine a point on it, but this “proposed program” represents an agency acting unconstitutionally. The people’s representatives, i.e., Congress, determined a decade ago that the cost and burden of individual reporting of malfunction MDRs is not necessary. The President duly signed this legislation into law on September 27, 2007.  Therefore, it is not for FDA to decide whether or not this approach is acceptable. As a constitutional matter, FDA (as part of the Executive Branch) is required to implement that statute. The agency, in other words, is required to faithfully execute the law, not brazenly flout it. See U.S. Const., Art. II, sec. 3.

FDA claims that its own failure to publish a list of excepted devices is what keeps the 2007 amendment to Section 519 from becoming effective. But, even if correct, this failure to act cannot excuse flouting the law for a decade and counting. It seems likely that a trade association or device firm could successfully obtain a writ of mandamus from a court requiring FDA to implement the statute as written. These writs are rarely granted, but this case is egregious enough that a court might issue one. FDA’s own 2015 pilot program and this new proposed program show that the agency is capable of developing an appropriate summary format and, in fact, has done so. The timing (quarterly) is set by statute and needs no agency decision making.

There is nothing more that needs to be done, except for FDA to identify the devices to be excepted. Contra FDA’s position, it is does not appear that this step necessarily prevents implementation of the statute. The law as written does not appear to make publishing a list of exceptions a condition precedent. Rather, it creates a general rule for class I and II devices but grants FDA broad continuing authority to create exceptions (by Federal Register publication and by letter).

Thus, it would be lawful and practically feasible for a court to order FDA to begin accepting summary quarterly reports, subject to exceptions for class I and II devices that FDA may designate by Federal Register publication or by letter. As a matter of discretion, a court could grant FDA a short stay to allow time to develop a list of exceptions before the order becomes effective.

In sum, this proposed program represents continued defiance of the law and a refusal to implement a statute enacted in 2007. FDA should not create the proposed program. Rather, it should immediately implement summary quarterly reporting as required by Section 519 of the FDCA.

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.

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.

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.

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.

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 21^st 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.

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.

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.

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.

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.

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.

“For Americans under the age of 50, drug overdoses are now the leading cause of death.” DOJ, Attorney General Jeff Sessions Delivers Remarks Announcing New Tools to Combat the Opioid Crisis (Nov. 29, 2017) (here).  “With evidence suggesting that nearly 80 percent of individuals addicted to heroin started out on opioid pain relievers, the link is clear that opioid prescriptions are driving this epidemic.”  Rep. Mark Meadows, Opioid Abuse Deterrence, Research and Recovery Act (here).  These statements by government officials, one representing the Trump Administration, the other from Congress, provide a sobering picture of the nationwide opioid abuse epidemic and form the basis for two new actions designed to stem the opioid crisis.  On November 29, 2017, Congressman Mark Meadows (R-NC) introduced H.R. 4482, the Opioid Abuse Deterrence, Research, and Recovery Act of 2017.  On the same day, Attorney General Jeff Sessions announced several Department of Justice (“DOJ”) and Drug Enforcement Administration (“DEA”) efforts also aimed at addressing the crisis.

Opioid Abuse Deterrence, Research, and Recovery Act of 2017

The Opioid Abuse Deterrence, Research and Recovery Act (“the Act”) would amend the Federal Controlled Substances Act (“CSA”) to require DEA-registered and state-licensed practitioners authorized to prescribe schedule II or III controlled substances to submit a “certification” to DEA that they will not prescribe a schedule II or III opioid “for the initial treatment of acute pain” unless the prescribed quantity is for less than seven days or falls within a State-established prescription limit. “Acute pain” is defined as “pain with abrupt onset and caused by an injury or other process that is diagnostically determined to have minimal risk of escalating in intensity.”  “Acute pain” under the Act does not include chronic pain, pain treated as part of cancer care, hospice, end-of-life care, or palliative care.

Under the Act, the certification would not prevent practitioners from prescribing opioids approved by FDA for opioid use disorder treatment; for immediate, post-operative pain relief; or for longer than seven days if prescribing is consistent “with a clear medical standard of care,” provided that the practitioner documents the prescription in the patient’s medical record and consults the State electronic health record system or prescription drug monitoring program.

The legislation would also require the FDA Commissioner to continue working with stakeholders and encouraging the development of abuse-deterrent opioids. In addition, to understand what led to the opioid crisis, the Act requires the Comptroller General to submit a report to Congress within two years on the health care policy changes that may have contributed to the increase in opioid overdoses and deaths.  The report must include:

1. A review of the federal health care-related legislative, administrative, and judicial decisions that affected access to pharmaceutical pain management strategies;
2. An analysis of the financial and non-financial costs and benefits of reversing or revising such decisions;
3. An analysis of the differences between State prescription drug monitoring programs;
4.  An analysis of the impacts of State and Federal prescribing limitations on patient medical outcomes; and
5. An analysis of the costs of using abuse-deterrent opioids compared to non-abuse-deterrent opioids.

Finally, the Act would require the FDA Commissioner to conduct a study on the feasibility of replacing the prescribing limits in the bill “with evidence-based clinical guidelines,” including a limitation “on the first opioid prescription for patients for an acute pain diagnosis” and “the incorporation into routine medical visits of evidence-based screening tools [to monitor] the misuse of opioids and other controlled substances.”

HPM Comments

We have long believed that effectively addressing the opioid epidemic requires focus on the physicians, doctors, dentists, and other practitioners who are the gatekeepers of public access to controlled substances. It is clear that overprescribing or inappropriate prescribing of controlled substances has been a significant cause in creating and sustaining the opioid abuse crisis.

The Act was clearly drafted with the Centers for Disease Control and Prevention’s (“CDC’s”) Guidelines for Prescribing Opioids for Chronic Pain in mind. While the CDC guidelines voluntarily limit opioid prescribing for chronic pain, the Act limits only the first or initial prescription of schedule II or III opioids to treat acute pain to seven days unless the practitioner fulfills requirements to prescribe for a longer period.  In fact, the Act does not reference prescribing for chronic pain.  Both the Act and the CDC guidelines focus on a theme that we believe is a significant contributor to the opioid abuse problem, that is, overprescribing or inappropriate prescribing of controlled substances.  However, the mechanics of having a prescriber provide a “certification” to DEA is problematic.  There are no details on how prescribers would “certify” (e.g., during the application or renewal process).  More importantly, the Act does not address the regulatory effect of certifying or, even more significantly, failure to comply with the certification.  It also fails to address whether practitioners will self-certify or obtain certification for submission from an official or unofficial organization.  It is worth noting that the CSA and DEA regulations related to sales of pseudoephedrine, provide for a certification by retail sellers that they will not sell in amounts greater than allowed under the CSA.  21 U.S.C. § 830(e)(1)(A)(vii); 21 C.F.R. §§ 1314.35-.42, 1314.101-.103.  Regardless, the Act’s requirements will make practitioners more carefully consider issuing a first opioid prescription for longer than seven days.  The inescapable downside is that some overly cautious practitioners may decline to issue necessary prescriptions to legitimate patients for longer than a week if they do not want to adhere to the requirements to do so or from fear that they will appear on DEA’s radar.

We believe that mandatory training and education for practitioners is more critical and an alternative would be to require that all practitioners who intend to be registered with DEA to prescribe Schedule II controlled substances should certify that they have received such training.

DOJ and DEA Initiatives

Attorney General Sessions announced several initiatives including a restructuring of DEA Field Offices to focus on the opioid abuse problem. The Attorney General announced that DOJ was awarding $12 million to law enforcement agencies in states hit hard by illegal prescription opioid, heroin, and methamphetamine activity.  DOJ awarded $7 million through its Anti-Heroin Task Force Program to investigate heroin and illegal opioid distribution in states with high per capita levels of treatment admissions for heroin and other opioids, and $5 million through the Anti-Methamphetamine Program to states that have “demonstrated numerous seizures of precursor chemicals, finished methamphetamine, laboratories, and laboratory dump seizures.” DOJ, Attorney General Sessions and Acting DEA Administrator Patterson Announce New Tools to Address Opioid Crisis (Nov. 29, 2017) (here).

Attorney General Sessions also announced the formation of a new DEA Louisville Field Division. This new office will strengthen DEA investigation and enforcement efforts under a single Special Agent in Charge in Kentucky, Tennessee, and West Virginia.  The geographic area served by the new Louisville Field Division was previously distributed among the Detroit, Atlanta, and Washington, D.C., Field Divisions.  The Attorney General anticipates that consolidating Kentucky, Tennessee, and West Virginia within a single jurisdiction “will produce more effective investigations on heroin, fentanyl, and prescription opioid trafficking, all of which have a significant impact on the region.” Id.

Lastly, the Attorney General directed every U.S. Attorney to designate an Opioid Coordinator for their district by December 15th. The Attorney General’s memo to all U.S. Attorneys instructed that Opioid Coordinators will be responsible for:

• Facilitating intake of cases involving prescription opioids, heroin, and fentanyl;
• Convening a task force of federal, state, local, and tribal law agencies to identify opioid cases for federal prosecution, facilitate interdiction efforts, and tailor their district’s response to the needs of their communities;
• Advising and training Assistant United States Attorneys on prosecuting opioid offenses;
• Maintaining statistics on opioid prosecutions; and
• Developing and evaluating the strategy to combat the opioid epidemic.

HPM Comments  

The creation of a new DEA Field Office focuses on several states particularly hard hit by the opiate abuse problem. Thus, it makes sense that DEA would consolidate resources to narrow the geographic scope to address these issues.  DEA drug investigations are better coordinated and more efficient when conducted within a single Field Division rather than multiple jurisdictions.  It also seems to us that the creation of an Opioid Coordinator should result in a more focused approach by U.S. Attorney offices to the opioid problem.  We note that in August 2017 the Attorney General had announced the formation of the Opioid Fraud and Abuse Detection Unit, which is a pilot program funding 12 prosecutors nationwide to focus on investigating and prosecuting health care fraud related to prescription opioids. Thus, DOJ/DEA is devoting significant resources to the fight against opioid abuse, which will likely result in more criminal, civil and administrative actions.

On November 16, 2017, FDA released a comprehensive policy framework for how the Agency intends to apply existing laws and regulations that govern regenerative medicine products, including human cells, tissues, and cellular and tissue-based products (HCT/Ps). The policy framework is set forth in a series of four guidance documents (2 final, 2 draft) that build upon the regulatory framework for these products, which was completed in 2005.  A guidance document cannot alter a regulation, but can clarify how FDA intends to enforce the regulation.

In a self-described balancing act, Commissioner Gottlieb notes that FDA hopes to foster new and innovative treatment options for patients, while creating a clearer regulatory framework that will allow for greater enforcement ability against those that fall outside of the framework (statement available here).  In addition, the policy framework also serves to implement regenerative medicine-related provisions of the 21^st Century Cures Act, including the Regenerative Medicine Advanced Therapy (RMAT) designation program (see previous coverage here).  Recall, under Section 3033 of the 21^st Century Cures Act, which added Section 506(g) to the Federal Food, Drug, and Cosmetic Act (FDC Act), a drug or biological product is eligible for RMAT designation if:

1. It meets the definition of a regenerative advanced therapy: “cell therapy, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the [PHS Act] and part 1271 of title 21, Code of Federal Regulations”;
2. The drug is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and
3. Preliminary clinical evidence indicates the drug has the potential to address an unmet medical need.

The effect of designation means that FDA must take actions to expedite development and review of the drug, including early interactions to discuss the potential for accelerated approval. In addition, a designated drug may be eligible for priority review or accelerated approval under current FDA regulatory standards, and if approved under accelerated approval, would be subject to a confirmatory study.

The final guidance documents, which were addressed in a previous accompanying blog post (here), are:

• Regulatory Considerations for Human Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use;
• Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception.

The two new draft guidances, which are the subject of this blog post, are intended to aid in bringing innovative, safe, and effective products to patients as efficiently as possible:

• Expedited Programs for Regenerative Medicine Therapies for Serious Conditions (“Expedited Programs for RMAT”);
• Evaluation of Devices Used with Regenerative Medicine Advanced Therapies (“Devices Used with RMAT”).

Draft Guidance #1: Expedited Programs for Regenerative Medicine Therapies

The “Expedited Programs for RMAT” draft guidance (RMAT draft guidance) describes several established programs, including Fast Track designation, Breakthrough Therapy designation, accelerated approval, and priority review designation, all of which are detailed in the more generally applicable guidance document entitled “Expedited Programs for Serious Conditions – Drugs and Biologics,” (May 2014) (see previous coverage here) as well as the newly established RMAT designation.

This draft guidance does not change the meaning of established terms such as “serious disease or condition,” “unmet medical need,” “surrogate endpoint,” “intermediate clinical endpoint,” and “clinically significant endpoint,” which were defined in the May 2014 Expedited Programs guidance. This new draft guidance does, however, address how CBER will apply the qualifying criteria for these expedited programs to regenerative medicine therapies, largely through examples.

Definition of RMAT

The RMAT draft guidance notes that regenerative medicine therapies are defined in section 506(g)(8) of the FDC Act, as “including cell therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such therapies or products, except for those regulated solely under section 361 of the Public Health Service Act (PHS Act) (42 U.S.C. 264) and [21 C.F.R. Part 1271].” RMAT draft guidance at 2.  In this draft guidance, FDA interprets section 506(g) to apply to gene therapies, including genetically modified cells, if they lead to a durable modification of cells or tissues (this policy was first announced by Commissioner Gottlieb in August 2017 – see previous coverage here).  FDA also interprets section 506(g) to permit RMAT designation of a combination product (biologic-device, biologic-drug, or biologic-device-drug) when the biological product component provides the greatest contribution to the overall intended therapeutic effects of the product (i.e., the primary mode of action is conveyed by the biological product component).

RMAT Benefits & Qualifying Criteria: Borrowing & Building upon Concepts from other Expedited Programs

The RMAT draft guidance clearly sets out the benefits and requirements of the RMAT designation by comparing and contrasting it to other, more-established expedited programs. With regard to benefits of RMAT designation – that FDA must take actions to expedite development and review of the product – the draft guidance interprets these statutory benefits as equatable to the benefits of the Fast Track and Breakthrough Therapy designation programs, which consist of:

• Opportunities for frequent interactions with the review team;
• Intensive guidance on an efficient drug development program;
• Organizational commitment involving senior managers; and,
• Consideration for rolling review of the BLA.

Then, with regard to the qualifying criteria for RMAT designation, the RMAT draft guidance establishes a broader approach to what qualifies as “preliminary clinical evidence” than FDA set out in the May 2014 Expedited Programs guidance. In addition to accepting more traditional clinical trials as preliminary clinical evidence, the RMAT draft guidance explicitly allows for well-designed retrospective studies and clinical case series that provide data systematically by treating physicians.  In addition, the RMAT draft guidance distinguishes what level of evidence is needed from Breakthrough Therapy designation, noting that RMAT does not require evidence that indicates the drug may offer substantial improvement over available therapies, which is a higher evidentiary bar.  This evidentiary flexibility comes with a key qualification.  The RMAT draft guidance requires the evidence to be generated using the actual product that is planned for clinical development, and not a related product.

RMAT-Specific Accelerated Approval

The RMAT draft guidance sets out that programs with RMAT designation are eligible for Accelerated Approval based on either (a) “previously agreed-upon surrogate or intermediate clinical endpoints that are reasonably likely to predict long-term clinical benefit” or (b) “reliance upon data obtained from a meaningful number of sites, including through expansion to additional sites, as appropriate.” RMAT draft guidance at 9.  While (a) is the traditional standard for Accelerated Approval under Subpart E, (b) is new and specific to RMAT-designated products, and the RMAT draft guidance specifies that this will depend on “whether the evidence of effectiveness is likely to be affected by a site-specific or investigator-specific bias, such that any conclusions regarding the product’s effectiveness could not be reliably generalized to other sites.” Id. This type of Accelerated Approval would likely result in requirements for post-approval clinical evidence about the product through expansion to additional sites.”

The other RMAT-specific Accelerated Approval provision that the RMAT draft guidance implements is the ability for such products to satisfy post-approval requirements via:

• The submission of clinical evidence, clinical studies, patient registries, or other sources of real world evidence such as electronic health records;
• The collection of larger confirmatory data sets as agreed upon during product development; or
• Post-approval monitoring of all patients treated with such therapy prior to approval of the therapy.

RMAT draft guidance at 10.

Considerations in Clinical Trial Design

Moving beyond the formal expedited programs, the RMAT draft guidance, in recognition that many regenerative medicines are being developed to address unmet medical needs in patients with serious conditions, including rare diseases, mentions innovative clinical trial designs that can support a BLA. Specifically, the RMAT draft guidance states that CBER will consider clinical trials that incorporate adaptive designs, enrichment strategies, and/or novel endpoints.

While this has already been done in other areas such as oncology drug development, the draft guidance proposes that, given the limited number of affected individuals in rare diseases that can participate in clinical trials, that several different investigational products may be compared to each other and a common control in a single study.

When selecting endpoints for clinical development, the draft guidance encourages sponsors to obtain input from the affected patient communities about endpoints that might be clinically meaningful – a principle supported by FDA’s Patient-Focused Drug Development Initiative (see previous coverage here).  As an example of such a patient-centric endpoint, the draft guidance discusses how improvement in performance of tasks that require visual function might be more appropriate than traditional measures of visual impairment in conditions that lead to advanced visual impairment; this is an apparent call-out of the endpoint Spark Therapeutics developed for its gene therapy program (see previous coverage here).

GMP Manufacturing Compliance Appears to be Waived

The RMAT draft guidance suggests that clinical trial data can be shared buy multiple clinical sites utilizing a common protocol if any individual site intends to seek BLA approval. While noting that the sites would also need to share a common manufacturing protocol, the RMAT draft guidance fails to address or even mention whether it expects to obtain comparability data for products manufactured at different sites (as it would for a commercial BLA), or whether it expects the clinical sites to expend the very substantial resources that would be needed to assure compliance with Good Manufacturing Practices (GMPs).  While FDA is to be applauded for its efforts in being creative, the resulting regulatory paradigm cannot result in disparate treatment of parties seeking BLA approval.

Draft Guidance #2: Devices Used with RMATs

The “Devices Used with RMAT” draft guidance (Device Evaluation draft guidance) was developed to satisfy the requirement set out in Section 3034 of the 21st Century Cures Act that FDA issue guidance clarifying how FDA will evaluate devices used in the recovery, isolation, or delivery of regenerative medicines.  Accordingly, this guidance discusses what FDA will consider when evaluating the devices used with RMATs.

Applying the Medical Device Regulatory Framework

The Device Evaluation draft guidance largely summarizes the existing medical device regulatory framework, asserting that devices used with RMATs are subject to the same processes and standards. For example, according to the draft guidance, like any other device, FDA has no predetermined list of intended uses or specific attributes that would result in a device used with an RMAT to be classified as a Class III device.  Also, FDA intends to apply the same regulatory principles to the development of devices used with RMATs, including the applicability of the “least burdensome” principle and determination of premarket pathway (e.g., 510(k), de novo, PMA, HDE).

Combination Device-RMAT Products

The Device Evaluation draft guidance attempts to simplify and streamline the application of regulatory requirements for combination device and cell or tissue products. The document articulates FDA’s intent that devices to be used with a specific RMAT may, together with the RMAT, be considered to be a combination product and be evaluated under a BLA at CBER.  However, stand‑alone devices that can be used for the recovery or delivery of approved RMATs (e.g., surgical tools, syringes) may be evaluated independently using premarket submission pathways for devices.  And, as such, FDA commits to apply the least burdensome principle to determine the “minimum required information” necessary for marketing authorization of that device.

Finally, in instances where the RMAT and specified delivery devices are separately packaged but labeled for use together, the two products may comprise a combination product. Where the delivery device may be used with multiple similar RMATs, separate marketing applications for each product may be required, however FDA intends to similarly simplify and streamline the regulatory requirements by reducing redundancy in data requirements (e.g., use RMAT IND studies to support approval or clearance of the device).

Use of a Device with One or More Types of Cell-Based RMATs

Because cell-based RMATs are likely to differ with regard to characteristics that can impact the way the RMAT interacts with different device materials (and, therefore, potentially impact its safety and effectiveness), such as cell viability, differentiation potential, activation state, and ability to respond to stimuli after administration, the Device Evaluation draft guidance discusses factors to consider when a device can be used with only one particular type of cell-based RMAT versus more than one type. Factors include (a) physical characteristics of the RMAT (e.g., cell size and sensitivity to shearing forces) and (b) demonstrated performance and compatibility.

Similarly, if during development, a given RMAT is demonstrated to have characteristics and use requirements that allow it to be administered with a class or subset of delivery devices without compromising safety and effectiveness, the RMAT may be approved on its own with appropriate labeling for use with devices. The draft guidance anticipates this will become more common as experience is gained over time with a specific RMAT or class of RMATs in different use settings.