By James E. Valentine & Karla L. Palmer –

We reported earlier this month that the Food and Drug Administration (FDA) amended its regulations to update the list of drugs that may not used in compounding under the exceptions set forth in sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FDCA). This list reflects those drugs that have been withdrawn or removed from the market because the drugs or components of such drugs have been found to be unsafe or not effective. See 21 C.F.R. § 216.24.  FDA is at it again with another proposed rule that would further amend this list.

In alignment with the votes of the June 2015 Pharmacy Compounding Advisory Committee (see meeting transcript here), the proposed rulemaking would add the following three drugs to the current list of 83 drugs: 

The notice provides a brief summary of the reasons why each drug is being proposed for inclusion. While the Pharmacy Compounding Advisory Committee also voted to include all drug products containing more than 325 mg of acetaminophen per dosage unit, FDA is still considering whether to propose adding it to the list.

Comments on the proposed rule can be submitted until January 3, 2017 here.

By John A. Gilbert, Jr. & Andrew J. Hull –

The Controlled Substances Act (“CSA”) and regulations promulgated by the Drug Enforcement Administration (“DEA”) provide for a right to an administrative hearing in matters where DEA seeks denial or revocation of a DEA registration to handle controlled substances. Such hearings are required to be open to the public. However, there is no routine publication identifying when such hearings will take place. The public, especially other DEA registrants, would benefit from such notice and the opportunity to observe the DEA administrative process.

Many of our readers are likely familiar with DEA’s hearing procedures (see here for an in-depth analysis). When the agency proposes to deny an application for registration or revoke or suspend an existing registration, the agency will issue the party an order to show cause (“OSC”), which provides the registrant a right to request a hearing on this action. In these cases, DEA regulations provide for the matter to be placed on the docket of DEA’s Office of Administrative Law Judges (“OALJ”) and for a hearing to be scheduled before an administrative law judge (“ALJ”).

These hearings are open to the public. See 5 U.S.C. § 556; Am. Bar Ass’n, A Blackletter Statement of Federal Administrative Law, 54 Admin. L. Rev. 1, 20 (2002). However, in most matters, the first time there is any mention in the public record of a hearing is after the hearing is concluded and, in fact, after the ALJ has issued a recommended opinion and the agency has published its final decision, known as a final order, in the Federal Register. According to a 2014 report by DOJ’s Office of the Inspector General (“OIG Report”), the average time it took to adjudicate a matter in 2012 was 371 days (down from an average of 616 days in 2008). OIG Report at 15. As such, a matter may be pending before the agency for a year (or longer) without any notice to the public until it is finally resolved.

Neither the CSA nor DEA’s regulations require that DEA notify the public of an upcoming hearing regarding the denial, revocation, or suspension of most registrations, though an exception applies to bulk manufacturers of a basic class of controlled substances listed in Schedule I and Schedule II. See 21 C.F.R. § 1301.35(b) (requiring notice of hearing in the Federal Register). Instead, DEA’s regulations allow for the notice of hearing to be provided in the OSC served on the individual party in lieu of publication in the Federal Register. See id. § 1301.45 (“The hearing will commence at the place and time designated in the order to show cause or notice of hearing published in the Federal Register . . . .”).

DEA administrative hearings are supposed to be open to the public. The problem is that the public is unlikely to even know that action is being taken against a particular registrant or that a hearing is taking place until after DEA publishes a final order. While DEA should make the existence of these cases and hearings known to the public, particularly because these hearings are public, DEA does not maintain any sort of public hearing docket. The only recourse for members of the public who are interested in following DEA’s ongoing hearings is 1) to contact DEA’s Office of Congressional & Public Affairs and blindly ask if there are any ongoing cases and whether there are any scheduled hearings, or 2) attempt to obtain this information through a FOIA request. We here at FDA Law Blog have tried both methods without much success.

Other federal agencies provide much greater access to information about hearings, along with the ability to view documents filed by the parties in the public docket. For example, the Environmental Protection Agency, the Federal Trade Commission, and the National Labor Relations Board all maintain current dockets that are available to the public on their websites (see here, here, and here).

We recognize that some DEA administrative hearings by their nature should not be totally “open” to the public. For example, some portions of cases may involve trade secrets or other confidential commercial information. However, we can also see some benefits to the public if DEA was to maintain a public docket or otherwise alert the public of ongoing administrative hearings.

First, a public hearing docket would generally create better public access to public information, one of the stated goals of the current administration. See Memorandum from President Barack Obama to Heads of Executive Departments and Agencies on Transparency and Open Government, 74 Fed. Reg. 4685 (Jan. 26, 2009). Second, access to such information could help other registrants fulfill their obligations under the CSA to help protect the public from the risk of diversion. For example, a pharmacy that learns that DEA has issued an OSC proposing to revoke the registration of one of its physician customers may choose to perform additional due diligence, including attending the hearing and/or no longer filling prescriptions for that physician as part of its corresponding responsibility. See 21 C.F.R. § 1316.04(a). Third, public knowledge of ongoing cases would allow interested parties to intervene or file amicus briefs at the discretion of the agency.

DEA has been criticized in recent years by the courts and industry as to its lack of transparency in operations. Providing access to DEA’s ongoing administrative hearing docket would be a great service to industry and the public as a whole, and would go a long way in ensuring greater openness. The most accessible and transparent method would be to maintain an online docket that, at the bare minimum, lists cases where a party has requested a hearing and details the hearing place and date.

DEA has indicated that it intends to significantly revise its hearing regulations. See OIG Report at 41, 46. Creating a hearing docket accessible to the public at the same time it introduces these new hearing regulations would be a significant and helpful step forward by DEA in promoting openness and transparency on matters that should already be open to the public.

By Karla L. Palmer & Andrew J. Hull – 

From time to time, we have posted on significant final orders in DEA administrative cases. We now plan to blog on these cases in a more regular fashion, partly because we have noted that a number of these “routine” revocation cases often also include some significant procedural rulings by the DEA Administrator. In fact, we have noticed an increase in such rulings involving disagreements between the administrative law judges and the Administrator.

Since September of this year, the DEA Acting Administrator has issued four final orders. Three of these cases involve DEA’s revocation of a registrant’s Certificate of Registration due to the registrant’s loss of authority to handle controlled substances in the state in which the registrant is licensed:

• Charles Syzman, D.O., 81 Fed. Reg. 64937 (Sept. 21, 2016)
• Richard J. Settles, D.O., 81 Fed. Reg. 64940 (Sept. 21, 2016)
• Kevin L. Lowe, M.D., 81 Fed. Reg. 64949 (Sept. 21, 2016)

These three cases are typically referred to as “loss of state authority cases,” in which the agency considers state authority to handle controlled substances a necessary condition of maintaining a DEA registration. These cases, as is typical, involve DEA’s summary disposition of the matter once DEA determines that the registrant lacks state authority. We will be blogging on a recently released fourth case, Edge Pharmacy, 81 Fed. Reg. 72092 (Oct. 19, 2016), in the near future.

In this post, however, we focus on the Acting Administrator’s arbitrary use of official notice without applying the requisite procedural safeguards to the respondent in the Settles case referenced above.

The Administrative Procedure Act (APA) allows an agency to take official notice in a final adjudication (somewhat analogous to judicial notice) of certain facts outside of the agency record. See 5 U.S.C. § 556(e) (“When an agency decision rests on official notice of a material fact not appearing in the evidence in the record, a party is entitled, on timely request, to an opportunity to show the contrary.”) The agency must note in its order that it is taking official notice of a material fact, and it must provide the parties an opportunity to refute that official notice.

In the past, DEA has relied on official notice of material facts outside of the agency record. For example, the agency will take official notice of a relevant action by a state medical or pharmacy board related to a registrant’s license or of proceedings in parallel criminal or civil cases. Typically, the Administrator will follow the appropriate procedure of stating it is taking official notice of a certain non-record fact and providing the parties a period of time to challenge that fact. See, e.g., Kamal Tiwari, M.D., 76 Fed. Reg. 71604, 71606 & n.4 (Nov. 18, 2011) (noting that the agency was taking official notice pursuant to 5 U.S.C. § 556(e) of the respondent’s licensing status listed on a state licensing website and providing the respondent with twenty days to dispute the fact).

Notwithstanding the Administrator’s past practice of providing a respondent notice and an opportunity to “show the contrary” consistent with the APA, the Acting Administrator, in the Settles case, appears to have ignored the APA’s statutory process for taking official notice. Dr. Settles, a physician, faced a series of allegations by DEA that he lacked state authority to hold a controlled substance registration, materially falsified an application to DEA, and engaged in various prescribing violations. He waived his right to a hearing, and the Acting Administrator issued the final order based on the record forwarded to him by agency counsel.

However, after the record had been forwarded to him, the Acting Administrator—on his own initiative—reviewed the medical licensing websites of New Mexico and Colorado and relied on these websites to further support the record evidence that Dr. Settles lacked state authority to practice medicine in those states. Settles, 81 Fed. Reg. at 64944 & n.13. The Acting Administrator failed, however, to take official notice of these facts, and he failed to provide Dr. Settles with any opportunity to challenge these findings.

The Acting Administrator’s disregard for the APA’s minimal notice requirements in relying on certain non-record facts is somewhat inexplicable, but not unprecedented. A similar failure to use the APA’s official notice procedures occurred in another case, Gregory White, M.D., 79 Fed. Reg. 24754, 24755 (May 1, 2014), in which the then-Deputy Administrator made a finding based on his own “internet search” on the California medical board’s website without taking official notice—or providing the respondent with opportunity to dispute—his finding as required by the APA. 5 U.S.C. § 556(e).

The ability to take official notice of facts is an important and helpful tool for an agency adjudication. But, like other provisions of the APA, it must be used within its statutory bounds in order to afford an aggrieved party necessary due process.  If DEA relies on certain non-record material facts in its adjudications, it too must go through the statutory process.

One final thought for consideration: The APA prohibits any employee “engaged in the performance of investigative or prosecuting functions for an agency in a case” from “participat[ing] or advis[ing] in the decision, recommended decision or agency review.” 5 U.S.C. § 554(d). Query as to where the boundaries would be in regard to the Acting Administrator’s actions and whether the Acting Administrator’s own internet searches for material facts constitutes an investigative function that would prohibit him from participating or advising in agency review of the record or in writing the final order. The same question would also be relevant to such actions by an administrative law judge.

By Kurt R. Karst –  

There are few things this blogger likes more (workwise at least) than having a hot cup of joe in the morning while reading through an FDA exclusivity decision. (Reading through the latest edition or supplement to the Orange Book while enjoying some coffee is also right up there on the top of the list.)  This blogger recently had one of those enjoyable  experiences after coming across a “new” – that is, “new” insofar as the decision was just publicly released – exclusivity decision buried in an FDA Approval Package (Summary Basis of Approval) for Inspirion Delivery Technologies, LLC’s (“Inspirion’s”) MORPHABOND (morphine sulfate) Extended-release Tablets, 15 mg, 30 mg, 60 mg, and 100 mg. FDA approved MORPHABOND under a 505(b)(2) NDA (NDA 206544) on October 2, 2015 for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

In an October 1, 2015 Exclusivity Letter Decision, the CDER Exclusivity Board examines whether or not a period of 3-year exclusivity the Agency apparently granted after approving  a Supplemental NDA (S-016) for AlPharma Pharmaceuticals, LLC’s (“AlPharma’s”) EMBEDA (morphine sulfate and naltrexone HCl) Extended-release Capsules (NDA 022321) should block the approval of MORPHABOND. We say “apparently” because the Orange Book does not show any unexpired period of 3-year exclusivity for EMBEDA in connection with the October 17, 2014 approval of S-016. That supplement revised the EMBEDA labeling to describe the results of data from in vitro and in vivo abuse potential studies. In any case, the 3-year exclusivity applicable to EMBEDA, which is approved for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, expires on October 17, 2017. 

The 505(b)(2) NDA for MORPHABOND was submitted to FDA in September 2014 and relies on FDA’s safety and effectiveness findings for MS CONTIN (morphine sulfate) Extended-Release Tablets (NDA 019516; approved on May 29, 1987), for which the Orange Book does not identify any unexpired period of patent or non-patent exclusivity. So, if the listed drug cited in the MORPHABOND 505(b)(2) NDA is not EMBEDA, then why are we even talking about a potential block on the approval of MORPHABOND?  Because, FDA interprets the FDC Act’s 3-year exclusivity provisions to apply regardless of a reliance tether.  This interpretation became clear within the past two years in the context of FDA’s consideration – and later court challenge – concerning Veloxis Pharmaceuticals, Inc.’s  (“Veloxis’”) 505(b)(2) application (NDA 206406) for ENVARSUS XR (tacrolimus) Extended-release Tablets.  In that case, FDA’s  determination, which was upheld in court, was that a period of 3-year exclusivity FDA granted in relation to an original NDA for a single-entity drug product for certain conditions of use blocked the approval of NDA 206406 for the protected conditions of use.  You can read up on that FDA decision and district court case here and here.

The EMBEDA-MORPHABOND exclusivity analysis differs from the Veloxis case analysis in two important respects. First, unlike EMBEDA, which contains two active ingredients, MORPHABOND contains only a single active ingredient.  Second, the period of 3-year exclusivity applicable to EMBEDA was granted in the context of a Supplemental NDA instead of an Original NDA.  Also, we should note that for those folks hoping that FDA might opine of the scope of EMBEDA’s 3-year exclusivity as it relates to abuse-deterrent formulations, you’re out of luck.  FDA states pretty early in the Agency’s 18-page Letter Decision that “[t]his memorandum only discusses whether the 3-year exclusivity for Embeda should block the approval of the MorphaBond NDA, and does not address the scope of Embeda’s exclusivity nor whether MorphaBond is eligible for its own period of exclusivity or the scope of any such exclusivity.” Oh well . . . another day perhaps.  But we have more on that below. 

For Supplemental NDAs, FDC Act § 505(c)(3)(E)(iv) provides the following with respect to 3-year exclusivity:

If a supplement to an application approved under subsection (b) [of this section] is approved after [September 24, 1984,] and the supplement contains reports of new clinical investigations (other than bioavailabilty [sic] studies) essential to the approval of the supplement and conducted or sponsored by the person submitting the supplement, the Secretary may not make the approval of an application submitted under subsection (b) [of this section] for a change approved in the supplement effective before the expiration of three years from the date of the approval of the supplement under subsection (b) [of this section] . . . .

Although FDC Act § 505(c)(3)(E)(iv) differs somewhat from FDC Act § 505(c)(3)(E)(iii) concerning Original NDAs, FDA says that the Agency “has taken a consistent approach to both types of applications in determining eligibility for 3-year exclusivity and scope.” From there, FDA lays out the two-step inquiry to determine the blocking effect of another sponsor’s period of 3-year exclusivity, both generally, and in the context of a combination drug product:

[I]n order to determine that a 505(b)(2) NDA is blocked because it seeks approval for a “change approved in a supplement” during another applicant’s 3-year exclusivity period, the 505(b)(2) NDA must be for a drug with the same active moiety as the drug with exclusivity. . . . If the 505(b)(2) application for a single-entity drug seeks approval for the same drug (active moiety) to which exclusivity has attached, then the second aspect of the scope inquiry applies.  To determine whether the 505(b)(2) NDA is barred, FDA must also determine what exclusivity-protected change was approved in the supplement.  To do so, FDA examines the conditions of approval supported by the new clinical investigations (other than bioavailability studies) that were essential to approval of the supplement.  If the 505(b)(2) NDA for a single-entity drug is for the same drug for the same exclusivity-protected change approved in the supplement, it will be blocked. . . .

[I]n determining whether a 505(b)(2) NDA is seeking approval for a “change approved in a supplement” to a fixed-combination and is therefore blocked by 3-year exclusivity for the supplement, FDA similarly limits its inquiry to applications that contain the same combination of active moieties as in the fixed-combination and examines the scope of the new clinical investigations essential to the approval and that were conducted or sponsored by the applicant. If the 505(b)(2) NDA is not seeking approval for a fixed-combination with the same combination of active moieties as the combination with exclusivity, it is not seeking approval for a change approved in the supplement and therefore cannot be blocked.

Based on that last paragraph in particular, you know the outcome of FDA’s EMBEDA-MORPHABOND exclusivity analysis. But here it is in FDA’s own words:

The change approved in the supplement (S-016) for Embeda is the change in conditions of approval for the drug containing the combination of active moieties approved in the Embeda NDA. Thus, the change approved in the supplement only bars approval of other 505(b)(2) NDAs for drugs containing the combination of active moieties approved in Embeda and that otherwise seek approval for the same exclusivity-protected conditions of approval as Embeda.  Because MorphaBond does not contain the combination of active moieties approved in Embeda, any approval of MorphaBond is not an approval for the “change approved in the supplement” (i.e., S-016) for which Embeda currently has exclusivity and no additional inquiry is required.  Therefore, we recommend that the exclusivity awarded to Embeda for S-016 should not block approval of MorphaBond.

Harkening back to an earlier note in the Letter Decision concerning the scope of EMBEDA’s exclusivity (quoted above), FDA states that “[i]f both Embeda and MorphaBond contained the same combination of the two active moieties morphine and naltrexone, we would need to evaluate the nature of the change approved in the NDA supplement and would need to determine which new clinical investigations were essential to approval of S-016.” But FDA did not have to go there. “We need not reach this aspect of the scope of inquiry here, however,” says FDA, “because Embeda and MorphaBond do not contain the same combination of active moieties.”

In addition to FDA’s statutory analysis and conclusion, the Agency discusses several other reasons supporting its determination. With respect to abuse-deterrence, FDA notes that the Agency’s “recommendation in this case is also consistent with the Agency’s efforts to foster the development of AD opioid products more generally. Because the science of abuse deterrence is still evolving and the Agency does not yet know which AD technologies will ultimately prove most effective in deterring opioid abuse, the Agency believes that, when the statute and regulations permit it, it is in the interest of public health to encourage development of multiple AD alternatives.”

Is FDA signaling with this comment how the Agency might determine, and what factors might affect, the scope of 3-year exclusivity for an abuse-deterrent drug product supported by clinical studies? Maybe. . . maybe not.  We hesitate to read too much into this FDA comment.  The fact is that FDA will only make an evaluation and determination when the Agency is faced with a hard set of facts. 

By Robert W. Pollock* & Kurt R. Karst –      

If there’s something strange in your neighborhood; Who you gonna call? If there’s something weird, and it don't look good; Who you gonna call? Unfortunately, FDA doesn’t have a Ghostbusters-type unit to call when there’s something strange or weird compliance-wise going on in your neighborhood that’s holding up final ANDA (or 505(b)(2) NDA) approval. (Oh, and you’re welcome for the earworm!)

The GDUFA program has spurred an increase in the number of inspections for generic drug applicants and the establishments identified in those applications. With the increasing number of inspections, comes an increase in Establishment Inspection Reports (“EIRs”) that need to be written by FDA investigators, cleared by their supervisors, and then reviewed and cleared by the Center for Drug Evaluation and Research’s Office of Compliance. As was noted in a recent post on the Lachman Consultants Blog, there appears to be a growing problem in getting timely resolution of compliance-related issues from the time the EIR leaves the field and up until FDA’s computer systems are updated to provide an acceptable finding.

Our firms (Hyman, Phelps & McNamara, P.C. and Lachman Consultant Services, Inc.) have been hearing a rising chorus of complaints about being stuck in what one applicant called the “Compliance Black Hole.” Another company referred to it as the “Endless Summer,” because that company has been trying to figure out when their compliance status will change in the FDA computers after having received no 483 observations on reinspection since March of this year.

Firms note that calls to FDA Regulatory Project Managers (“RMPs”) or Regulatory Business Project Managers yield the same response: “There is nothing we can do until the computer system is updated.” Many of these responses come after the issuance of a Complete Response Letter (“CRL”) stating that the only outstanding issue is resolution of the status of a facility’s compliance. So the firm is stuck in a waiting mode.   Simply calling the Office of Compliance has yielded basically the same result. Clients are telling us that they do not receive return calls (or that they are simply told to sit tight and wait).

Trying to find a sympathetic ear at FDA is also difficult, particularly when a firm is ready to launch but for the final compliance clearance and approval action. In addition, we have heard from firms with potential date-certain launch dates (either day-181 dates or settlement dates) that they were informed by FDA officials that the compliance status of their application remains unresolved in the Agency’s computer system, notwithstanding the fact that the sponsor was informed by an FDA field investigator that there were either no 483 observations following inspection, that a completed EIR was forwarded to CDER finding satisfactory the firm’s responses to inspectional observations, or that an approval recommendation had gone forward. While we recognize we don’t always have the full picture when we hear these types of observations from sponsors, the frequency of occurrence of such complaints is increasing in dramatic fashion. Last week alone, Lachman Consultants received four inquiries about such issues. Each company expressed exasperation in not being able to get an answer other than “You just have to wait!”, and asked the same question: “Who can I call at FDA to discuss the issues?”

There’s no easy answer to that question. Depending on your level of exasperation, you might start at the top of the FDA Office of Compliance food chain, or perhaps at the Office of Process and Facilities, which is in the Office of Pharmaceutical Quality. (Here’s the CDER List of Key Officials in case you need it.)  It’s unclear how many applications are being delayed because they are stuck in the “Compliance Black Hole” . . . probably dozens, and perhaps several score. But, as noted above, a simple call to FDA is unlikely to do the trick in removing a compliance status block on approval. Instead, a sponsor might consider escalating the issue by requesting a meeting with the relevant FDA officials. After all, he who screams the loudest might be more likely to get FDA’s attention.      

* Mr. Pollock is Senior Advisor, Outside Director to the Board, Lachman Consultant Services, Inc., and is an author of the Lachman Consultants Blog.

For almost 40 years FDA has allowed device firms to promote their device while a 510(k) submission is still pending.  Yet, questions about how to apply this policy still remain.  In an article newly published in MedTech Insight, titled "Promoting Your 510(k)-Pending Device: 5 Questions About FDA's Policy," Hyman, Phelps & McNamara, P.C.'s Jeffrey K. Shapiro answers some of the most frequently asked questions.   

By Riëtte van Laack –

A couple of weeks ago, the Food Safety Inspection Service of the USDA (FSIS) announced the availability of an updated compliance guideline regarding animal-raising claims. The previous guideline dated from 2002.

Traditionally, the FSIS has interpreted the Federal Meat Inspection Act (“FMIA”) and Poultry Products Inspection Act (“PPIA”) to require that labels for federally inspected meat and poultry products be approved before the meat and poultry products are marketed, except when the label is generically approved. Labels with animal-raising claims are not eligible for generic label review and must be submitted to FSIS. Examples of claims include: “Raised Without Antibiotics,” “Organic,” “Grass-Fed,” “Free-Range,” “Raised without the use of hormones.” FSIS allows such claims only if the company submits documentation to support the claim(s). Moreover, FSIS determines whether a claim will be false or misleading. For example, since under U.S. law, chickens may not be treated with hormones, FSIS will not approve a claim “no hormones administered” unless the claim includes the statement: “Federal regulations prohibit the use of hormones in poultry.”

Depending on the claim, the documentation needed to support the animal-raising claim generally includes:

• A detailed written description explaining the controls used for ensuring that the raising claim is valid from birth to harvest or the period of raising being referenced by the claim;
• A signed and dated document describing how the animals are raised (e.g., vegetarian-fed, raised without antibiotics, grass-fed) to support that the specific claim made is truthful and not misleading;
• A written description of the product-tracing and segregation mechanism from time of slaughter or further processing through packaging and wholesale or retail distribution;
• A written description for the identification, control, and segregation of non-conforming animals or products; and
• A current copy of the certificate if the claim is certified by a third party, e.g., organic certification or non-GMO verified project.

The updated guideline provides a number of examples of animal-raising claims and the documentation required for the sample claims. It also addresses what, if any, documentation is required when an establishment wants to “duplicate” animal-raising claims from purchased products/ingredients incorporated into the establishment’s product.

FSIS issued the updated guideline in response to questions it received about animal-raising claims. Much of the information likely already was available in some other format such as on askFSIS, and in policy statements. Although comments may be submitted until December 5, 2016, FSIS advises establishments that wish to use animal-raising claims to use the guideline immediately.

By James E. Valentine –

In what can only be described as a success story, FDA’s Patient-Focused Drug Development (“PFDD”) initiative has opened the doors to hundreds of patients, caregivers, and other patient representatives to share their experiences with their diseases and conditions with FDA. This series of disease-specific meetings has helped set what FDA refers to as the “therapeutic context” for its regulatory decision-making for drugs and biologics.  PFDD gives patients an opportunity to help CDER and CBER review staff better understand the burden and impacts of their condition and their experiences with treatment options.  This amplification of the patient perspective allows for the evaluation and inclusion of information that is not conveyed by reading the medical literature and textbooks.  This input is not limited to the day of the meeting itself, but is memorialized in a “Voice of the Patient” report that is in turn made available to FDA review staff.  This report importantly includes a draft benefit-risk assessment framework, which provides patient input in a format that can be used during drug approval decisions.

Four years into what FDA refers to as its “pilot,” the Agency announced a milestone for the program: it held its 20th PFDD meeting – the number of meetings FDA committed to host under the fifth authorization of the Prescription Drug User Fee Act (“PDUFA V”).  While that was the minimum required number, FDA will hold four more PFDD meetings by the end of FY2017, which is when PDUFA V expires. 

While the PFDD meetings were underway, FDA negotiated a draft commitment letter for PDUFA VI.  As proposed, FDA will not be committing to host any additional PFDD meetings.  This begs the question: what is the future of PFDD?

(This is not a new question; see one of our previous discussions here.)

The Future: Externally-Led PFDD Meetings?

The most obvious answer is that PFDD meetings are not going to stop, but will instead be carried on by patient organizations instead. Because there are many more disease areas than can be covered by the 20+ FDA meetings under PDUFA V, in December 2015 FDA invited patient organizations to host their own PFDD meetings.  This parallel effort involves patient organizations submitting a Letter of Intent (“LOI”) to FDA, after which point they may proceed with planning and hosting an externally-led PFDD meeting. 

While this program is still getting off the ground, early examples have demonstrated that well-planned and executed externally-hosted meetings can be a successful alternative to FDA-hosted meetings:

• On November 16, 2015, the Amyloidosis Research Consortium (ARC) in collaboration with the Amyloidosis Foundation and Amyloidosis Support Groups hosted an “Amyloidosis Patient Forum with FDA.” Although this meeting occurred before FDA formally announced a process for hosting externally-led PFDD meetings, the agenda mirrored that of FDA’s PFDD meetings. As a result of the meeting, on June 7, 2016, ARC submitted a “Voice of the Patient” report to FDA, which follows the same format as the FDA reports (the report can be found here).
• On September 15, 2016, the Myotonic Dystrophy Foundation (MDF) hosted the first official externally-led PFDD meeting, which also had an agenda that followed the format of FDA’s PFDD meeting. MDF has committed to develop a “Voice of the Patient” report to submit to FDA.

Both the amyloidosis and myotonic dystrophy meetings had the key elements that made the FDA meetings so successful: large turnouts by their patient communities; a well-constructed agenda that included a mixture of patient panels, polling questions, and moderated audience discussion; webcast/livestream participation; and, attendance by key FDA officials, including remarks from some. In addition, the externally-drafted “Voice of the Patient” report will serve as an important resource to FDA review staff. 

So do Externally-Led PFDD Meetings Fit Within PDUFA VI?

While PDUFA VI does not explicitly address whether FDA will continue to accept LOIs for externally-led PFDD meetings, there are a number of activities under the “Enhancing the Incorporation of the Patient’s Voice in Drug Development and Decision-Making” commitment that could accommodate the program. Alternatively, the draft commitment letter indicates that FDA may be moving away from the PFDD meeting model:

FDA will develop a series of guidance documents to focus on approaches and methods to bridge from initial patient-focused drug development meetings, like those piloted under PDUFA V, to fit-for-purpose tools to collect meaningful patient and caregiver input for ultimate use in regulatory decision making.

This could include more qualitative methodological approaches, such as surveys of patient communities and other technologies to capture patient experiences (e.g., Patient-Reported Outcome measures).

Could PFDD Meetings Reemerge Under FDASIA Section 1137?

On February 19, 2016, FDA published a report on publicly-submitted stakeholder views on potential “strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions,” which the Agency is required to develop and implement under the Food and Drug Administration Safety and Innovation Act (“FDASIA”) Section 1137, “Patient Participation in Medical Product Discussions.”  The report states that several comments recommended the facilitation of more systematic patient engagement by the Office of the Commissioner across FDA Centers responsible for human medical product regulation.  If there is a demand by patient stakeholders for the initiative to continue, one plausible possibility would be for PFDD to transition to the Office of the Commissioner where patients could share their experiences with CDER, CBER, and CDRH. 

If that happens, I guess the initiative would have to be renamed Patient-Focused Medical Product Development or PFMPD. Or just keep it as PFDD…

By Jeffrey K. Shapiro –

In 1976, FDA first began comprehensive regulation of medical devices. Among the new statutory provisions, there was one requiring persons registering with FDA to list all marketed devices.  Each device on the list was to be accompanied by a copy of the label and package insert (see Section 510(j) of the Federal Food, Drug, and Cosmetic Act).

Within two years, FDA had decided that requiring a copy of the label and package insert was not going to be practical or useful. FDA said that it might not need the information when submitted and, unless consistently updated, it might be out of date when needed.  Also, there was no practical way to compile, update or access the information, much less provide routine public access.  Typically, the device listings were submitted on paper and manually transcribed into data storage on reels of magnetic tape and floppy disks.  Therefore, in lieu of requiring compliance with the actual statutory requirement, FDA required device firms to maintain a historical file of labels and labeling available upon FDA’s request.

Fast forward almost 40 years. The Internet is now pervasive and electronic storage is robust and easily searchable.  Taking advantage of the now-established technology, FDA is proposing to give new life to the requirement in Section 510(j).  As it happens, Section 510(j) has remained on the books the entire time even though not enforced for all of these years.

The foregoing history is recounted in the preamble to FDA’s new proposed rule. What are the features of the proposed rule?  Those who are interested will, of course, want to read the entire proposal.  The most important features can be summarized as follows:

• The new rule would be limited to Class II and Class III devices intended for home use. It would not apply to devices intended for use in professional health care facilities, such as hospitals, nursing homes, clinical laboratories, or physician offices.
• The label and package insert would be electronically submitted each time device listing is electronically submitted or updated, which is required at least annually. The information could be in a PDF format, which may some day transition to FDA’s Structured Product Labeling (SPL) format.
• The statutory term “package insert” would be defined by regulation (for the first time ever) to cover the information that is delivered to the lay home user with the device. It would not include information for device installers, servicers, or health care professionals. This limitation arises from the chief aim of the rule, which is to help lay home users find device instructions.
• FDA would archive the information in an easily searchable database. One particular advantage would be keeping information on file for older devices even after a manufacturer discontinues marketing (and may have stopped posting the package insert on its web site).

FDA gives two primary reasons for the limited reach of the new rule. The first is the agency’s belief that Class II and Class III home use devices have a higher risk of misuse due to lost or misplaced labeling and operating instructions.  The second is that FDA would like to gain experience maintaining this type of database before applying it more broadly.  Presumably, the program could be expanded if it proves beneficial.  (One quibble with the proposed definition of package insert is that the definition is appropriate for this rule but would have to be revised if the rule were expanded.  It would be better to define it properly and then limit the type of package insert required under this rule.)

The preamble to the proposed rule supplies little hard data to back up the supposed benefits. It does indicate that in-home device cause a significant number of serious adverse events (based on 2014 data) and also FDA has received reports of lost labeling for high risk in-home devices.  But the preamble does not provide data to establish that lost or missing instructions actually cause or contribute to a significant percentage of serious adverse events.

Even so, the proposed rule still seems generally like a good idea. FDA’s core function is regulating labeling and so the notion that device manufacturers would submit current labeling to FDA makes sense.  Indeed, it was part of the original statutory design in 1976 for all manufacturers to do so, even though FDA found it impractical for many decades.  In 1976, moreover, Congress probably was more concerned about giving FDA access for regulatory purposes.  Nonetheless, perhaps the best part of the proposed rule is enabling FDA to provide the public with reliable access to current labeling.  Intuitively, the availability of easy-to-find instructions for use is likely to contribute to safe and effective device usage, even if supporting data for this proposition are currently scarce.

FDA also proposes over time to add links to relevant information for affected devices, such as recalls and manufacturer notifications. It is easy to imagine that FDA might eventually be able to build out a very robust public database with full device life cycle information, one that is easily accessible to the agency and device users, whether in the home or in professional healthcare facilities.  The painful UDI adoption process now underway may help make this database even more granular.  If that is the future, and one hopes that it is, then this proposed rule is a useful step in that direction.

By Karla L. Palmer –

In a move unprecedented in recent memory, on October 13, 2016, DEA published a Withdrawal of Notice of Intent to Temporarily Place Mitragynine and 7- Hydroxymitragynine (i.e., kratom) in schedule I of the Controlled Substances Act.

As background, a little over a month ago, on August 31, 2016, DEA’s Administrator issued a notice of intent to temporarily schedule in schedule I of the Controlled Substances Act (CSA) the opioids mitragynine and 7-hydroxymitragynine. These opioids are the main active constituents of the plant kratom.  DEA took this action based on the Administrator’s finding that placement of these opioids into CSA’s schedule I was “necessary to avoid an imminent hazard to the public safety.”  Thus, any final order would impose administrative, civil, and criminal sanctions and regulatory controls applicable to schedule I controlled substances on the manufacture, distribution, possession, importation, and exportation of, and research and conduct of instructional activities of these substances

As DEA’s August 31st Notice of Intent stated, 21 U.S.C. § 811(h)(4), requires the Administrator to notify the Secretary of HHS of his intention to temporarily place a substance into schedule I of the CSA. The Administrator transmitted notice of his intent to place mitragynine and 7-hydroxymitragynine in schedule I on a temporary basis to the Assistant Secretary on May 6, 2016.  The Assistant Secretary responded on May 18, 2016, advising that, based on FDA’s review, there are “currently no investigational new drug applications or approved new drug applications” for mitragynine and 7-hydroxymitragynine. The Assistant Secretary also stated that HHS did not object to the temporary placement of mitragynine and 7-hydroxymitragynine in schedule I of the CSA.   DEA noted neither substance is currently listed in any CSA schedule, and there were no approved new drug applications or investigational new drug applications for the substances.

Importantly, to temporarily schedule a substance in schedule I, because of its “imminent hazard to the public safety,” the Administrator must consider only three of the eight statutory factors typically required for scheduling a controlled substance under 21 U.S.C. § 811(c): the substance's history and current pattern of abuse; the scope, duration and significance of abuse; and what, if any, risk there is to the public health. 21 U.S.C. §

811(h)(3)

. Consideration of these factors includes actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution. Id. § 811(h)(3). Temporary scheduling is only permitted for schedule I substances: those that have a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision. Id. § 812(b)(1).  Thus, considering the history and current pattern of abuse, the scope, duration and significance of abuse; and risk to the public health, as addressed in the Notice, DEA published its Notice of Intent concerning the substances, stating that after 30 days it could publish a final rule temporarily scheduling the substances for a period of up to two years.  DEA noted also that, although it believed the Notice was not subject to APA notice and comment requirements, the Administrator would “take into consideration any comments submitted by the Assistant Secretary with regard to the proposed temporary scheduling order.”

Although we are unsure yet whether the Assistant Secretary submitted comments, DEA stated in its October 13th Notice of Withdrawal of Intent that it had “received numerous comments from members of the public challenging the scheduling action and requesting the  Agency consider those comments and accompanying information before taking further action.  A check of the docket (DEA-442) did not reveal that any comments had been publicly posted, although DEA stated in its withdrawal notice it is reviewing comments it received by email and mail, and those comments do not need to be resubmitted.  

A simple Google search of “Kratom,” however, shows a glimpse of the widespread and significant public outcry resulting from DEA’s emergency scheduling attempt. Others reported last week that DEA faced pressure from industry and Capitol Hill, including letters to DEA signed by several members of Congress requesting DEA to permit adequate time for stakeholders to comment or otherwise weigh in on the propriety of DEA’s temporary scheduling decision.  

DEA’s Notice of Intent to Withdraw states the Agency will now receive from FDA its scientific and medical evaluation, and scheduling recommendation for the substances. See 21 U.S.C. § 811(b).  (DEA noted it previously requested FDA’s evaluation (which FDA is required to provide within a reasonable time under § 811)).  Not only do we look forward to reading FDA’s scientific and medical evaluation, and scheduling recommendation, but we also assume the public will file numerous comments addressing both the propriety of DEA’s decision and of kratom use generally.  DEA has established a comment period for docket number DEA-442, which will remain open until December 1, 2016. 

By Serra J. Schlanger & Alan M. Kirschenbaum –

We previously reported (here and here) on two opinions handed down by Judge Rya Zobel of the Federal District Court for the District of Massachusetts construing the discount safe harbor under the Federal health care program antikickback statute (AKS).  In both cases, Judge Zobel held that the buyer’s discount disclosure requirement under the safe harbor cannot be met unless the government requests the disclosure.  In other words, government action is a necessary condition of protection under the safe harbor, despite the fact that the government typically does not request such documentation.  There have been noteworthy developments in both of these cases.

In one of the cases, United States ex rel. Herman v. Coloplast Corp., et al. (Case 1:11-cv-12131-RWZ), the United States filed a Statement of Interest on October 6 that includes a footnote directly refuting Judge Zobel’s interpretation.  In footnote 2, the government states “if the Secretary or a State agency requests disclosure, the buyer must provide the requested information to retain protection under the safe harbor. If, however, the Secretary or a State agency has not requested disclosure, safe harbor protection remains available if all other requirements are met. . . .” (emphasis added).  The DOJ’s view is consistent with that expressed by PhRMA in its amicus brief, and is also consistent with the long standing position of the OIG.  One can only hope that the DOJ and PhRMA will succeed in enlightening the Court on the proper interpretation of the discount safe harbor’s disclosure requirement.

Less helpfully, the DOJ reiterated the position set forth in its previous Statement of Interest in this case that, “if a reduction in price is conditioned on more than a simple purchase, it is not a mere discount” and therefore is not eligible for protection under the discount safe harbor. According to the DOJ, “[n]othing in the AKS or HHS-OIG regulations suggests that a manufacturer and a distributor can hide a personal services contract within a discount, particularly a discount based on volume or market share.” 

We wonder how the DOJ’s interpretation applies to manufacturer formulary rebates that are ubiquitous in both commercial and Medicare Part D plans, under which manufacturer rebates are conditioned not simply on purchases but also on the payor providing certain services – i.e., maintaining a specified formulary status for the drug and enforcing the plan formulary. Under the DOJ’s restrictive view, these rebates presumably would not be eligible for protection under the discount safe harbor.  The DOJ’s interpretation might also exclude many value-based purchasing arrangements that are gaining momentum in the marketplace as cost-saving measures, such as performance-based rebates triggered by specified clinical outcomes, rather than simply purchases.  Indeed, CMS is proposing to initiate value based purchasing models under Medicare Part B.  It is uncertain whether the DOJ’s restrictive interpretation of the discount safe harbor could subject these arrangements to liability under the AKS. 

In the second case before Judge Zobel, United States ex rel. Banigan v. Organon USA, Inc., et al. (Case 1:07-cv-12153-RWZ), defendant Omnicare filed a reply brief on October 7 in further support of its motion for reconsideration or interlocutory appeal.  Omnicare is challenging Judge Zobel’s interpretation of the disclosure requirement of the discount safe harbor, discussed above.  Omnicare’s brief correctly notes that the ability of manufacturers and their customers to enter into discounts and rebate arrangements depends on the availability of the discount safe harbor.  Citing to our September 14 blog post, Omnicare adds that “the Court’s interpretation of the [discount safe harbor’s] second prong ‘eviscerates the safe harbor, rendering it virtually useless’ to charge-based providers.”  We will continue to closely follow the Organon and Coloplast cases in this blog.

By Riëtte van Laack –

The Sunscreen Innovation Act (SIA) was enacted in 2014. It amended the FDC Act to provide specific deadlines for FDA’s review of time and extent applications (TEAs ) for sunscreen active ingredients.  Thus far, FDA has proposed sunscreen orders for all eight pending requests, all of which tentatively determined that the active ingredients are not GRASE and that more data are necessary to allow FDA to determine otherwise.

Pursuant to mandate of the SIA, about 11 months ago, FDA issued four draft guidances related to sunscreen time and extent applications (see our previous post here). On Friday, October 7, 2016, FDA issued the final versions of two of the four guidances, the guidance on withdrawal of sunscreen TEAs, and the guidance on requesting advisory committee review.

The final guidance on withdrawal of a sunscreen TEA is virtually identical to the draft guidance. Only two comments were submitted.  Both commenters asserted that FDA has no authority to publish a non-GRASE decision when the sponsor withdraws the TEA after a proposed sunscreen order has been published.  FDA disagreed and maintains its position that because the information was submitted as part of a public process, the information remains part of the public record.   In April, 2016, FDA issued a proposal regarding withdrawal of TEAs, consistent with this position.  Since FDA has issued proposed orders for all eight pending requests, unless the sponsors submit supplemental data supporting GRASE status, sponsors cannot prevent FDA from publishing non-GRASE decisions for all eight ingredients.  

The final guidance on requesting advisory committee review also contains no surprises and is largely identical to the draft guidance. Again, only two comments were submitted.  The final guidance provides additional detail regarding the timing of the request for a meeting.  FDA recommends that the sponsors request the meeting “at the time they submit their initial data package, or no later than at the time of the filing determination” and for sponsors of pending requests are recommended to submit their request at the time they submit their supplemental data package. 

By James E. Valentine & David C. Clissold –

Nearly two years after releasing its Notice of Proposed Rulemaking (“NPRM”), and with about 900 comments from the public to consider, the National Institutes of Health (“NIH”) has published its Final Rule on clinical trials registration and results reporting.  These regulations provide specificity and expand upon the self-implementing requirements that have been in effect since the Food and Drug Administration Amendments Act (FDAAA) was passed in 2007.  The Final Rule largely maintains the proposed rule’s requirements for submitting registration and summary results information, including adverse event information, for specified clinical trials for drugs, biological, and device products to ClinicalTrials.gov (for a detailed overview of these requirements, see our previous coverage here). 

However, FDAAA Section 801 delegated decision-making on several key issues to NIH’s rulemaking, including expansion of results reporting for unapproved drugs and the submission of summary narratives and trial protocols (see our previous discussion of deferred topics here).  While there is much to digest in the 177-page Final Rule, this blog post will highlight how the Final Rule addresses these previously unanswered questions, as well as other key changes from the NPRM.

Submission of Results Information for Products Unapproved, Unlicensed, or Uncleared for Any Use

FDAAA Section 801 requires the submission and posting of registration information and results information for applicable clinical trials of approved, licensed, or cleared products (“approved products”), as well as the submission of registration information and posting requirements for an applicable clinical trials of unapproved, unlicensed, or uncleared products (“unapproved products”). In addition, the statute deferred to NIH as to whether to require the submission of results information from applicable clinical trials of unapproved products, whether or not approval was sought.  The Final Rule maintains the NPRM’s proposal to require the submission of results information for applicable clinical trials of products unapproved for any use (i.e., any indication), regardless of whether FDA approval is or will be sought or obtained. 

The Final Rule does make a change to the NPRM regarding the applicability of this requirement to applicable clinical trials of unapproved products with a primary completion date before the effective date (January 18, 2017) that are subsequently approved for the use studied in the applicable clinical trial. Under the proposed rule, results reporting was required if the results submission deadline due to FDA approval was after the effective date of the rule.  This proposal was scaled back so that, now, such trials are not subject to the new results reporting requirements.

Submission of Technical and Non-Technical Results Summaries Not Required

FDAAA Section 801 required NIH to determine whether a summary of the clinical trial and its results in a technical or non-technical summary could be included as part of required results reporting on ClinicalTrials.gov “without being misleading or promotional.” In response to public comments expressing concerns regarding the difficulty of trial sponsors to write accurate, non-promotional, and non-misleading summaries,  NIH decided to not require either type of narrative summary of results in the Final Rule.  NIH notes that future rulemaking may be warranted if additional research can determine a way for such summaries to be produced reliably and consistently. 

Submission of Protocols and Statistical Analysis Plans

FDAAA Section 801 instructed NIH to require a full protocol or information on the protocol for the trial to the degree it “may be necessary” to help evaluate the results of the trial. While the NPRM laid out several ways this could be achieved, NIH was compelled by public comments arguing that protocols provide information to better contextualize the reported results information.  For example, protocols provide more detail about methods of participant selection, randomization, masking, and assignment to arms; methods of collecting data; specific information about clinical trial interventions, such as other elements of care provided; and assessment of adverse events.  Thus, the Final Rule requires submission of the full protocol and the statistical analysis plan (“SAP”), if it is a separate document, as part of the results reporting, and both will be posted with the results. 

NIH also recognized some concerns raised in public comments about protecting personally identifiable information about individuals participating in or involved in conducting the clinical trials. To address these, the Final Rule allows the responsible party to redact information about individual clinical trial participants.  In addition, the trial allows redaction of identifying information about individuals involved in conducting the trial, as long as it is not otherwise required to be submitted as part of the clinical trial information.

Potential Legal Consequences of Non-Compliance

While not addressed in the NPRM, the Final Rule includes a new section that addresses the legal consequences of non-compliance. This new section describes potential civil or criminal actions, civil monetary penalties, grant funding actions, and judicial remedies that may be pursued as a result of a responsible party’s failure to comply with the regulations.  In addition, this section describes certain non-compliant activities that will be considered prohibited acts under the Federal Food, Drug, and Cosmetic Act that can result in certain of the various types of enforcement action against the responsible party. 

Although not included in the text of the regulation, the preamble to the Final Rule specifies that, under the statute, NIH will include notices on ClinicalTrials.gov denoting non-compliance. These notices include: failure to submit required information; submission of false or misleading information; penalties imposed, if any; whether the information has been corrected; and, failure to register the primary and secondary outcomes.

Effective Date, Compliance Date, and Applicability Determinations

The Final Rule extends the effective date proposed in the NPRM from 45 calendar days to 120 calendar days from the date the Final Rule was filed for public inspection in the Federal Register, or January 18, 2017. However, the compliance date remains the same in the Final Rule, at 90 calendar days after the effective date, or April 18, 2017. 

To aid in determining the applicability of the requirements set out in the Final Rule, the process for making this determination was clarified. Specifically, the registration requirements that apply to an applicable clinical trial are determined by the date on which the trial is initiated (i.e., the actual start date).  Meanwhile, the results reporting requirements that apply to an applicable clinical trial are determined by the date on which the trial reaches its actual primary completion date.  Lastly, the marketing status of a product will be determined based on its marketing status on the primary completion date. 

NIH-Funded Research

NIH also announced, in conjunction with the Final Rule, a final policy that would extend similar registration and reporting requirements to all clinical trials funded by NIH, regardless of whether they are subject to FDAAA.

By Andrew J. Hull –

There has been an interesting development in the ongoing prosecution of a slew of former officers and employees of the New England Compounding Center (NECC). As you may recall, the NECC was responsible for shipping allegedly contaminated compounded steroid epidural products nationwide, allegedly resulting in widespread sickness and death (see our previous post here).

Last week, the federal district court in Massachusetts (Stearns, J.) dismissed the indictment as it pertained to two former NECC employees, Kathy Chin and Michelle Thomas. The indictment charged them with felony counts of dispensing drugs into interstate commerce without a valid prescription.  Under 21 U.S.C. § 353(b)(1), a drug is deemed misbranded while held for sale if it is dispensed by a pharmacist without a valid prescription.  The felony charge requires an intent to defraud or mislead.

The controversial aspect of indicting Chin and Thomas is that they were not pharmacists dispensing prescriptions in the way most people would understand that description. Rather, they were actually in charge of the final check of prescription drug packages for accuracy as to name, address, and contents. 

The indictment alleged that Chin and Thomas had to know these prescriptions were phony because the patient names were so unlikely, including celebrities, famous athletes, and fictional characters (e.g., “David Letterman,” “Jay Leno,” “Dale Earnhardt,” “Tony Tiger,” “L.L. Bean,” and “Filet O’fish”). The government took the position that their incidental role in checking the packages for the phony prescriptions made them just as guilty of the crime as the pharmacists who dispensed the drugs without a valid prescription.

The court, however, held that the FDC Act did not provide fair notice to the defendants that their activities would constitute “dispensing.” The court noted that the FDC Act does not define the word “dispensing,” and held that the word should be given its meaning in common parlance within the statutory context:

In the world of pharmacology, a pharmacist engages in the act of dispensing when she “fill[s] a medical prescription.” Stedman’s Medical Dictionary (28th ed. 2014).  In other words, a pharmacist dispenses a drug when she acts in her role as a licensed professional authorized to fill (put together) a medical prescription for delivery to a patient.

Order at 8.

Absent the constitutional due process that fair notice provides to defendants informing them that their activities are covered under a criminal statute, the court ruled that the indictment, as it pertained to Chin and Thomas, failed. Specifically, the court held that because the defendants’ conduct was only “incidental” to the activity of dispensing, the FDC Act did not provide them with fair notice that their conduct violated the FDC Act:

Returning to basics, the issue in this case is one of fair notice. Would a reasonable person, even a reasonable pharmacist, understand from the indictment that by matching orders to packages prior to their being shipped, she was criminally liable for participating in the filling of a prescription that she had never approved (or is even alleged to have seen), and as a result was guilty of dispensing (misbranding) the prescribed drug with the intent to defraud?  The answer, as best as I can determine, is that she would not.  Absent allegations of conduct amounting to fair notice of a crime under the [FDC Act], the indictment fails.

Id. at 11-12.

Criminal cases entertaining constitutional due process challenges of fair notice under the FDC Act are rare. See, e.g., Kordel v. United States, 335 U.S. 345, 348-49 (1948); United States v. Zenker, No. 94-50616, 1996 WL 468614 (9th Cir. Aug. 16, 1996).  We could only locate a single case in the long history of the FDC Act that actually dismissed criminal charges under a “fair notice” due process theory. United States v. Geborde, 278 F.3d 926, 932 (9th Cir. 2002) (holding that the FDC Act’s “held for sale” provision did not provide fair notice to a doctor that his conduct of providing friends with homemade (i.e., misbranded) drugs for free was covered under the FDC Act).  

Recent Supreme Court case law has expanded the “fair notice” concept as a check against government regulation and prosecution of people in the regulatory context. See generally FCC v. Fox Television Stations, Inc., 132 S. Ct. 2307 (2012).  We anticipate there may be other challenges to FDA enforcement cases on this ground.

By James E. Valentine & Karla L. Palmer –

On October 6, 2016, the Food and Drug Administration (FDA or the Agency) amended its regulations to update the list of drugs that may not used in compounding under the exceptions set forth in sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act (FDCA).  This list reflects those drugs that have been withdrawn or removed from the market because the drugs or components of such drugs have been found to be unsafe or not effective. See 21 C.F.R. § 216.24.  FDA originally published its withdrawn or removed list back in 1999.  FDA states its primary focus since the 1999 final rule (and the 2014 proposed rule) has been on whether the drug products are unsafe.  FDA notes that it may add to the list to include products that are not effective, or update the list to include additional products that are unsafe.  These updates will continue to occur through notice and comment rulemaking; FDA will also (typically) only add to or modify the list after consultation with the Pharmacy Compounding Advisory Committee (PCAC).  FDA also states it will create and maintain a web page about proposed drugs that it is considering adding to the list.   A single list will apply to both sections 503A and 503B.

Revisions to the Withdrawn or Removed List

Consistent with the July 2, 2014 proposed rule (which we covered here), public comment thereon, and after soliciting input from FDA’s PCAC, the final rule adds the following  24 drugs to the withdrawn or removed list, which is codified at 21 C.F.R. § 216.24:

In addition, the rule creates an exception for ophthalmic solutions of bromfenac. No drugs previously listed were removed from the list. 

Exceptions to the List  

While most drugs on the list may not be compounded in any form, in FDA’s preamble to the rule, the Agency clarifies two exceptions. First, when FDA provides an exclusion for a particular formulation, indication, dosage form, or route of administration for a drug on the list (e.g., ophthalmic solutions of bromfenac), this indicates that there is an approved drug containing the same active ingredients that has not been withdrawn or removed from the market because it has been found to be unsafe or not effective.  As such, that particular formulation, indication, dosage form, or route of administration that is expressly excluded from the list may still be compounded under sections 503A and 503B.  

Second, some drugs are listed only with regard to certain formulations, concentrations, indications, routes of administration, or dosage forms because they have been found to be unsafe or not effective (e.g., oral and parenteral diethylstilbestrol containing 25 mg or more per unit dose).  As such, other formulations, concentrations, indications, routes of administration, and dosage forms not on the list may still be compounded.  

In addition, the preamble notes that just because a drug is on the withdrawn or removed list “does not mean it is banned completely and absolutely from compounding.” If warranted, FDA states that drugs on this list could be made available under an expanded access program under 21 C.F.R. part 312, subpart I.