Getting an early jump on winter, between September 29 and October 2, CDRH issued a blizzard of new guidance documents. All eleven of these guidances were issued based on commitments from MDUFA IV.  These guidances consist of:

• four guidances regarding user fees for each type of submission (510(k)s, PMAs/BLAs, 513(g)s, and de novos);
• four guidances regarding administrative procedures and review time frames for premarket submissions (510(k)s, PMAs, de novos, and CLIA categorization);\
• a guidance regarding responding to premarket submission deficiencies in a least burdensome manner (which we blogged on earlier here);
• a revised guidance regarding 517A appeals; and
• a revised pre-submission guidance.

A full list of the guidances can be found here.

The first eight guidances are mainly administrative and are consistent with the commitments described in MDUFA IV, which we summarized in our FDARA Summary. The revised 517A appeals guidance reflects the change from FDARA indicating that a substantive summary must now include an explanation regarding how the least burdensome requirements were considered and applied in the decision being appealed.  Given the boilerplate nature of least burdensome explanations, it is not clear that this will be of any real value.  In addition, the guidance adds that decisions regarding breakthrough decisions (granting/denial) are considered significant decisions, which can be appealed under Section 517A.

The revised pre-submission guidance has a few notable changes. These modifications primarily relate to meeting timing, scheduling of meetings, and meeting minutes.  The timeframe for most pre-sub types set forth in Table 1 of the guidance are unchanged.  However, consistent with MDUFA IV, the timeframe for general pre-submission has been modified.  Specifically, in the original 2014 guidance, FDA committed to having a meeting/teleconference (if requested) within 75 to 90 days from receipt of the pre-submission.  The guidance also committed to providing written feedback within 3 business days of the meeting/teleconference.  In the updated guidance, FDA now commits to generally holding meetings within 60 to 75 days of submission receipt and providing written feedback within 70 days of receipt or 5 calendar days prior to a meeting/teleconference, whichever is sooner.  The meeting timeframe is not much different from what was happening in practice prior to release of the new guidance.  In our experience, FDA has, when possible, been holding meetings within 60 to 75 days.  However, written feedback has sometimes been delayed, occasionally coming just a day before the meeting.  Receiving written feedback 5 calendar days before the meeting should allow submission sponsors more time to digest FDA’s written comments and prepare for their meetings.

The guidance also provides a more formalized process for scheduling pre-submission meetings. Sponsors will still need to propose three dates for a meeting/teleconference in its pre-submission.  Within 15 days of receipt, FDA will still conduct its acceptance review, which is unchanged.  Once accepted, FDA will either confirm one of the sponsor’s proposed dates or propose two alternative dates, which should be within 75 days of submission receipt.  FDA will work with the sponsor to set a meeting date between acceptance of the submission and 30 days after submission receipt.  If a meeting has not been scheduled by day 40, an FDA manager will call the sponsor to resolve the scheduling conflict.  In our view, this process was a much-needed addition to the guidance.  With all of its other obligations, FDA has sometimes fallen short on setting pre-submission meetings in a timely fashion.  We hope these new procedures will help facilitate timely meeting scheduling.

Another notable change is that the 2014 guidance said that an applicant could request the manner in which is preferred to receive feedback (i.e., meeting, teleconference, in writing). The guidance also said “please note that FDA will ultimately decide the means of communicating the feedback, but will consider the desired method requested in the Pre-Sub.”  This quoted language has been removed in the revised guidance.  While we are only aware of a couple of instances in which FDA did not provide the feedback in the manner requested by the sponsor, we are happy to see that this language has been removed.  The removal should mean that FDA will provide the type of feedback requested by the sponsor.

The final change relates to meeting minutes. The revised guidance indicates that at the beginning and end of a pre-submission meeting/teleconference, the sponsor must affirmatively state that it will draft minutes and provide meeting minutes to FDA within 15 calendar days of the meeting.  For those that have been to a pre-sub meeting recently, this is a statement that FDA typically makes at the start and end of the meeting.  Putting the responsibility on the sponsor may seem unusual; however, at the recent AMDM IVD Focus Meeting (October 5, 2017 in Los Gatos, CA), Elizabeth Hillebrenner, M.S.E., Associate Director for Programs and Performance at OIR indicated that FDA has had issues with pre-submission sponsors submitting meeting minutes.  Ms. Hillebrenner noted that issues generally include not submitting minutes at all, not submitting within 15 days, or submitting minutes that are inadequate to document the meeting (e.g., insufficient detail).  With this critique in mind, it makes sense that FDA would want manufacturers to acknowledge that they will draft and submit minutes within 15 days.  This procedural change should not be burdensome for sponsors.  Presumably, if a manufacturer forgets to make the requisite statement at the beginning and end, FDA will remind the company.

Ms. Hillebrenner’s comments should also remind all pre-submission sponsors of best practices when it comes to meeting minutes. Sponsors should ensure that at least one person at the meeting is solely responsible for taking minutes.  The minutes should not be a transcript of the meeting.  However, they should be sufficiently detailed to document the discussion that occurred.  Well drafted meeting minutes benefit both the sponsor and FDA ensuring that there is an adequate, detailed account of the meeting.

There is a long history and established precedent in Drug Enforcement Administration (“DEA”) administrative cases in the use of summary dispositions (i.e., determination without a hearing) related to the loss of state licensing authority (e.g., state medical or controlled substance license) (see our previous post here). In such cases, agency precedent dictates that revocation is required as a matter of law. See Serenity Café, 77 Fed. Reg. 35027, 35027-28 (June 12, 2012).  In other words, because DEA views state licensure of practitioners to be a condition precedent to holding a DEA registration, a registrant without state licensure cannot, as a matter of law, continue to hold a registration. See 21 U.S.C. §§ 802(21), 823(f).

We previously commented on the fact that DEA had recently granted summary disposition in a case, Richard J. Blackburn, D.O., 82 Fed. Reg. 18669 (Apr. 20, 2017), involving, in part, an alleged material falsification of a DEA application for registration (see our previous post here). In our opinion, this was a troubling decision to expand the use of summary dispositions based on a factual issue and not as a matter of law, thus denying the registrant the opportunity to present evidence on the circumstances related to the allegation.

A more recent case, however, extends this trend and includes the apparent establishment of an “egregiousness” standard that DEA may use to justify future summary dispositions and, in the process, deny registrants the due process contemplated under the Controlled Substances Act (“CSA”) and regulations promulgated by DEA.

On October 5, 2017, DEA published a final order by the (now former) Acting Administrator revoking a physician’s registration through summary disposition. In this case, William J. O’Brien, III, D.O., 82 Fed. Reg. 46527 (Oct. 5, 2017), a physician had been convicted of over one hundred felony counts related to controlled substances, including one for distribution of controlled substances resulting in death.  The practitioner was sentenced to a total term of imprisonment of 30 years.  Not surprisingly, the state licensing authority also suspended his medical license (i.e., lack of state authority).

The government sought—and was granted—summary disposition on the lack of state authority. As noted above, this is a well established precedent.  However, the Acting Administrator also upheld the ALJ’s ruling granting the government’s motion for summary disposition on the felony conviction grounds.  In granting summary disposition on the felony conviction grounds, the ALJ noted the recent Blackburn decision in which the Acting Administrator held that the Government was entitled to summary disposition on the grounds of material falsification.

This use of summary disposition based on a felony conviction related to a controlled substance (21 U.S.C. § 824(a)(2))—in our experience— is unprecedented and a trend that could lead to the erosion of the due process rights of DEA registrants and applicants.

The Acting Administrator acknowledged that the use of summary disposition was out of the ordinary:

In contrast to a practitioner’s loss of his state authority, this finding does not mandate the revocation of his registration on this ground [(i.e., felony conviction related to controlled substances)] and the Agency has held that a conviction is not a per se bar to registration (as is the loss of state authority). . . . Here, however, Respondent’s criminal conduct, which involves 120 felony convictions for unlawful distribution, including for unlawful distribution resulting in death, is so obviously egregious that revocation is warranted.

Id. at 46529. The Acting Administrator also admitted that “ordinarily a respondent who has been convicted of a felony subject to section 824(a)(2) is entitled to present a case as to why his registration should not be revoked (or his application denied).” Id.

However, the Acting Administrator appears to have created a new standard in stating that a hearing was unnecessary because the conduct was so “egregious.” While he noted that the practitioner had not alleged “evidence to show why he can be entrusted with a registration nor raised any contention that he acknowledges his misconduct and has undertaken remedial measures,” the physician never had the opportunity to hear or question the government’s case or to present actual evidence in his defense. Id. The bottom line:  DEA (government counsel, ALJ, and Acting Administrator) all agreed that the physician’s criminal convictions were so egregious that a hearing was useless.  In the Agency’s view, there was nothing that the physician could raise in his defense that could persuade the Acting Administrator against revocation.

The problem is that the CSA, DEA regulations, and DEA’s own precedent allow a respondent to rebut the government’s prima facie case by a showing of (1) acceptance of responsibility and (2) remedial actions. See, e.g., Mireille Lalanne, M.D., 78 Fed. Reg. 47750, 47777 (Aug. 6, 2013).  The respondent may also attempt to mitigate the severity of the wrongdoing by providing context, such as ill health or other circumstances.  Most importantly, the CSA states that, prior to revoking a registration based on a violation of 21 U.S.C. 824(a) (including felony conviction related to controlled substances), the Administrator must provide the respondent with an opportunity for a hearing under the Administrative Procedure Act (“APA”). See 21 U.S.C. § 824(a)(c).

DEA’s failure to provide the physician in this case with an opportunity for a hearing to present testimony and/or documentary evidence on the felony conviction grounds (21 U.S.C. § 824(a)(2)) flies in the face of the due process protections afforded to respondents by the APA and CSA. It also deviates from other cases where DEA did afford the respondents the opportunity for a hearing even though they had been convicted of felonies related to controlled substances.  In some of these cases, DEA refused to revoke a registration (or deny an application) in light of the respondent’s remedial case, despite a finding that the respondent has been convicted of a felony related to controlled substances. See, e.g., Kimberly Maloney, N.P., 76 Fed. Reg. 60922, 60922-23 (Sept. 30, 2011) (granting application of physician with felony conviction for obtaining controlled substance by means of forged prescription); Michael S. Moore, M.D., 76 Fed. Reg. 45867, 45867-68 (Aug. 1, 2011) (suspending—not revoking—registration of doctor convicted of felony manufacturing of controlled substance); Mary Thomson, M.D., 65 Fed. Reg. 75969, 75971-52 (Dec. 5, 2000) (continuing registration with restrictions of physician with felony conviction for obtaining controlled substances by fraud); Edson W. Redard, M.D., 65 Fed. Reg. 30616, 30618-19 (May 12, 2000) (continuing registration with restrictions of physician with felony conviction for obtaining controlled substance by fraud).

DEA’s decisions in this case and the Blackburn case reveal a troubling trend.  The Agency has now provided some precedent for obtaining a revocation or application denial through summary disposition based on grounds other than loss of state authority (so far, material falsification and felony conviction)—grounds that are by statute to be reviewed (at the request of the respondent) through the hearing process.  21 U.S.C. § 824(c).  Now it appears DEA may decide that the alleged violations are so “egregious” that it need not provide the required due process rights.  So, for example, DEA could decide that a registrant’s recordkeeping is so deficient on its face and as a matter of law, that the registrant should not be given the opportunity to present evidence in his/her defense or to accept responsibility and demonstrate remedial action.

In conclusion, as required by law and agency precedent, DEA should limit summary dispositions to matters of law with no factual dispute. Otherwise, despite potentially  “egregious” actions, registrants should be provided the due process required under the law, regulations, and agency precedent.

On October 9, 2017, California Governor Jerry Brown signed into law a bill (SB 17), which imposes new notification and reporting requirements on pharmaceutical companies, health care service plans, and health insurers. Among the many reporting obligations under SB 17, we describe below only those obligations associated with drug pricing. Other state legislatures have undertaken similar efforts intended to promote transparency in drug pricing (see our posts on a Nevada bill, here, and a Vermont law, here). Maryland enacted a law that prohibits an “unconscionable increase” in the price of a generic drug, which is the subject of ongoing litigation (see our posts here and here).

Manufacturer Reporting: WAC Increases of 16% or More

Pharmaceutical manufacturers with prescription drugs purchased or reimbursed by a state purchaser, licensed health care service plan, health insurer, or pharmacy benefit manager (PBM) have reporting requirements under SB 17. It is important to note that, under California law, manufacturers include not only those entities that produce prescription drugs, but also those that repackage prescription drugs as well as certain types of entities that distribute those drugs. See Cal. Bus. & Prof. Code § 4033. A manufacturer with any prescription drugs that have a wholesale acquisition cost (WAC) of more than $40.00 for a course of therapy must notify each purchaser if it will increase the WAC more than 16%. The 16% increase threshold includes the current increase and the cumulative increases that occurred within the previous two calendar years prior to the current year. Notice must be given to the purchaser at least 60 days prior to the planned effective date of the increase. PBMs receiving notice of WAC increases greater than 16% must notify their contracted large public and private purchasers (covering >500 lives) of such increases as well. California’s Office of Statewide Health Planning and Development (OSHPD) Legislative Affairs office indicated that the effective date for these notification requirements and other requirements which do not specify a delayed implementation date is January 1, 2018.

Starting in January 2019, prescription drug manufacturers must report to the OSHPD on a quarterly basis the following information for each drug with an increase in WAC of over 16%:

• A description of the financial and nonfinancial factors used to make the decision;
• A schedule of WAC increases for the drug for the previous five years;
• If the drug was acquired by the manufacturer in the last five years, other information about the WAC history, purchase price, and the previous owner;
• Patent expiration information;
• Whether the drug meets the definition of multiple source drug, innovator multiple source drug, noninnovator multiple source drug, or single source drug under the Medicaid Drug Rebate Program (42 U.S.C. § 1396r-8(k)(7)(A));
• A description of the “change or improvement in the drug, if any, that necessitates the price increase”; and
• The volume of U.S. sales for that drug in the previous year.

Manufacturer Reporting: New Drugs

If a prescription drug manufacturer plans to introduce a new prescription drug to market at a WAC that exceeds the threshold set for a specialty drug under the Medicare Part D program, it must notify OSHPD in writing within three days after release of the drug in the commercial market. The specialty tier threshold for Calendar Year (CY) 2017 (and CY 2018) is $670 per month. CMS, Announcement of CY 2018 Medicare Advantage Capitation Rates and Medicare Advantage and Part D Payment Policies and Final Call Letter and Request for Information, 152-153 (Apr. 3, 2017).

The notification must include the following information:

• A description of the marketing and pricing plans used in the launch of the new drug in the United States and internationally;
• The estimated volume of patients who may be prescribed the drug;
• Whether the drug was granted breakthrough therapy designation or priority review by FDA prior to final approval; and
• The date and price of acquisition if the drug was not developed by the manufacturer.

Additional Manufacturer Reporting Provisions

OSHPD will publish the information obtained under the two sections above on its website at least quarterly. SB 17 states that the “information shall be published in a manner that identifies the information that is disclosed on a per-drug basis and shall not be aggregated in a manner that would not allow identification of the drug.”

Manufacturers may limit the information reported under the two sections described above to information that is otherwise in the public domain or that has been made publicly available.

Finally, manufacturers may incur civil penalties of $1,000 per day following the notification period for noncompliance.

Health Insurer and Health Plan Reporting Related to Prescription Drugs

With regard to health insurers and health care service plans that must, under California law, report rate information to either the state Department of Managed Health Care (DMHC) or Department of Insurance (DOI), SB 17 requires reporting to DMHC or DOI the following cost information for all covered prescription drugs no later than October 1 of each year, starting in 2018:

• The 25 most frequently prescribed drugs;
• The 25 most costly drugs by total annual plan spending; and
• The 25 drugs with the highest year-over-year increase in total annual plan spending.

DMHC and DOI must compile this information into a public report “that demonstrates the overall impact of drug costs on health care premiums.” The report must be published on their websites by January 1 of each year.

SB 17 also requires health plans with large group health care service plan contracts and health insurers with large group health insurance policies to disclose the following information for covered generic, brand, and specialty drugs dispensed at a plan, network, or mail order pharmacy for outpatient use:

• The percentage of the premium attributable to prescription drug costs for the prior year for each prescription drug category;
• The year-over-year percentage increase in per-member, per-month total health plan spending for each prescription drug category;
• The year-over-year increase in per-member, per-month costs for drugs, compared to other components of the health care premium;
• The specialty tier formulary list;
• The percentage of the health care premium attributable to prescription drugs covered under the medical benefit;
• Information on the use of a PBM, if any, along with information on which components of prescription drug coverage are managed by the PBM; and
• The PBM or other manager name(s).

We will continue to track implementation of SB 17 and similar legislation regarding drug pricing transparency in other states.

* Law Clerk

Today (October 12, 2017) FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee unanimously recommended approval of Spark Therapeutics, Inc.’s Biologics License Application (BLA 125610) for Voretigene Neparvovec (also called LUXTURNA), a gene therapy for the treatment of patients with vision loss due to confirmed biallelic RPE65 mutation-associated retinal dystrophy (i.e., an inherited retinal dystrophy that always progresses to blindness). This is the first true gene therapy to come before an FDA advisory committee.  Today’s action boosts not only the hopes of those with this specific genetic disorder, but also sparks hope among all those with incurable genetic diseases.

“Lessons Learned” include:

• A single pivotal efficacy study of modest scope (n=31) may be sufficient.
• Dose optimization and drug safety assessments, even for highly innovative gene therapy, need not be necessarily more extensive than those for other similarly rare diseases.
• Videographic evidence of subjects negotiating a dimly-lit maze shows sponsor and FDA commitments to preference for a patient-centric primary endpoint measure.
• This measurement of a critical daily patient function is even more noteworthy here in this clinical area that has very well established quantitative measures (e.g., visual acuity and visual field which were secondary endpoints).

Global Observation:

The Office of Tissues and Advanced Therapies within the Center for Biologics Evaluation and Research at FDA exhibits reasonable and appropriate “flexibility” in its review of this first true gene therapy seeking FDA registration.

Today’s action may be the Spark that illuminates the way forward for all those with incurable genetic disease.

Sponsors commonly receive a request for additional information (AI) during Food and Drug Administration (FDA) review of a 510(k) submission, de novo classification request, or premarket approval application. In some cases, a sponsor may conclude that one or more AI requests calls for information that is not relevant or necessary to fulfill the statutory criteria for clearance or approval. Such requests do not comply with the requirement in the Federal Food, Drug, and Cosmetic Act for FDA to require the “least burdensome” scientific evidence necessary to support clearance or approval.

In these situations, a useful first step is to turn to FDA’s guidance, Developing and Responding to Deficiencies in Accordance with the Least Burdensome Provisions – Guidance for Industry and Food and Drug Administration Staff. An updated version of this guidance was issued on September 29, 2017, in fulfillment of a Medical Device User Fee Amendments of 2017 (MDUFA IV) Commitment Letter. It aims to help FDA review staff and supervisors request additional information that represents the “minimum required” to make their regulatory decisions. See FD&C Act, Sections 513(i)(1)(D)(ii), 513(a)(3)(D)(iii), and 515(c)(5)(B).

The guidance was originally issued 17 years ago (on November 2, 2000). It applies to FDA’s requests for additional information, which they refer to as deficiencies, needed to complete reviews of premarket approval (PMA), humanitarian device exemption (HDE), premarket notification [510(k)] and De Novo premarket submissions. As in the original, the guidance sets forth principles for FDA in writing deficiency letters and provides a suggested format for industry responses to FDA deficiencies. A sponsor can use these principles when explaining to FDA why a particular AI request is not “least burdensome.”

New to the guidance are a set of six guiding principles for FDA review staff:

1. Information unrelated to the regulatory decision should not be part of the decision-making process.
2. Alternative approaches to resolving regulatory issues should be considered to optimize the necessary time, effort, and resources involved in developing a response.
3. Deficiencies should request the minimum (i.e., least burdensome) amount of information necessary to adequately address the identified issue in the most efficient manner at the right time. The balance between premarket and postmarket should be considered to determine when information should be provided to address the identified issue.
4. Major deficiencies are those based on least burdensome principles that, if not resolved, will preclude a favorable decision on the marketing application. Major deficiencies should only be included if their resolution is necessary in order to reach a final decision regarding the marketing authorization.
5. If the Agency is including minor deficiencies identified during the review in the deficiency letter, the Agency should identify these requests separately from major issues, and whenever possible, attempt to resolve minor questions/issues interactively. Minor deficiencies are FDA requests that can be resolved in a straightforward manner, but that need to be addressed to meet regulatory requirements or to prevent potential misbranding or adulteration. In general, the Agency should not issue a formal deficiency letter if only minor deficiencies remain, but instead should attempt to resolve them interactively.
6. FDA may also include additional considerations that are suggestions, recommendations, or requests that are not expected to preclude a favorable decision on the marketing application. Because additional considerations are not expected to preclude a favorable decision, they do not require an applicant response.

Also new is the requirement from the MDUFA IV Commitment Letter for all deficiency letters to undergo supervisory review prior to issuance. Additionally, the recommendation for FDA staff now includes the following: “where appropriate, reference to an applicable section of a final rule, final guidance, and/or an FDA recognized standard (unless the entire or most of the document is applicable). When the deficiency cannot be traced in the manner above and relates to a scientific or regulatory issue pertinent to the determination, FDA will cite the specific scientific issue and the information to support its position.”

Like the original guidance, the updated guidance provides a recommended format for responding to deficiencies. These recommendations include:

1. 1. Restate the identified Agency issue; and
2. Provide one of the following:
3. the information or data requested;
4. an explanation why the issue is not relevant to the marketing authorization decision; or
5. alternative information and an explanation describing why the information adequately addresses the issue.

One of the biggest challenges in responding to an FDA deficiency letter is persuading FDA to actually accept to accept either alternative information or a sponsor’s explanation as to why additional information is not necessary. These are areas where sponsors and reviewers often struggle to reach agreement. Although some examples are provided, the new guidance provides no new insights on how best to approach this perennial problem. In our experience, the most persuasive case will be based on a deep understanding of the technology and careful attention to the concern FDA is raising. Simply reiterating the “least burdensome” mantra back to FDA reviewers is unlikely to yield positive results.

All in all, while the “least burdensome” requirement has never had a lot of teeth in it, we are hopeful that the new guiding principles, specific references and supervisory review will help keep FDA’s deficiency letters focused on the minimum information necessary to reach a regulatory decision.

In early 2016, CMS issued a proposed rule to test new models for the payment of drugs and biologics under Medicare Part B (see our previous post here). The current statutory payment methodology for most drugs under Medicare Part B is the Average Sales Price (ASP) plus six percent. The proposed five-year pilot program would have tested an alternative payment methodology of ASP + 2.5% plus a flat fee of $16.80 (Phase I) and the effect of four different value-based pricing methods (Phase II). The pilot was to have been conducted under the authority of Section 1115A of the Social Security Act, which authorizes CMS’s Center for Medicare and Medicaid Innovation (CMMI) to test innovative payment models to reduce program expenditures.

On October 4, CMS announced, in a short Federal Register notice, that it has withdrawn the proposed rule. The notice states that the Agency received 1,350 public comments and that “a number of commenters expressed concerns about the proposed model.” Because of the “complexity of the issues related to the proposed model design and the desire to increase stakeholder input,” CMS decided to abandon the proposed pilot. The notice concludes with a statement about how the Agency wants to “ensure agency flexibility” in re-examining these issues.

We will continue to track this and any new initiatives concerning drug payment methodology proposed under CMMI.

* Law Clerk

On September 28, 2017, the Department of Health & Human Services’ Office of Inspector General (OIG) released its internal report on FDA’s domestic food facility inspections.  The “key takeaway”: “FDA should do more to ensure that the food supply is safe by taking swift and effective action to ensure the prompt correction of problems identified at domestic food facilities.”

In the previous (2010) review, OIG found that FDA inspected less than a quarter of domestic food facilities each year, and that many facilities had not been inspected in 5 years or more. OIG also found that FDA did not always take action against facilities with significant inspection violations or take steps to ensure the violations were corrected. According to the 2017 OIG report, two key recommendations from OIG’s 2010 review remain outstanding, i.e., (1) take appropriate action against facilities with significant inspection violations and (2) ensure that those facilities correct the violations.

FSMA requires FDA to increase the frequency of its inspections of domestic food facilities. Specifically, FSMA mandates that FDA inspect high-risk facilities at least once during the initial 5-year inspection cycle and then at least once every 3 years for subsequent cycles. (A facility would be high risk based on a number of factors including association with outbreaks, recalls or prior food safety related violations.) For the remaining facilities, the non-high risk facilities, FSMA requires that FDA inspect them at least once during the 7-year initial inspection cycle and at least once every five years for subsequent cycles. Prior to FSMA, there were generally no timeframes for food facility inspections.

While executing its inspection plan, FDA discovered that information about food establishments was not always up-to-date or sufficient. For a not-insignificant percentage (more than 25%) of the facilities, FDA’s inspection failed because the facility was either out of business or otherwise not in operation at the time of the visit. These failed inspections were counted as completed inspections. OIG determined that FDA has no policy to assure that such inspections do occur.

OIG determined that FDA is on track to meet the requirements for the first round of inspections (for the high risk facility inspections, FDA is in fact ahead of the schedule as it completed inspections for almost all those facilities within three years). FDA likely can meet the requirement for the second round of inspections of the high-risk facilities (to be completed within three years). However, OIG questions the Agency’s ability to meet the second (5-year) inspection cycle for the non-high-risk facilities.

OIG further determined that FDA uncovered significant (official action indicated or OAI) violations in one to two percent of the inspected facilities. In 22% of those instances, FDA allegedly did not take any action. Moreover, in the instances that FDA did take action, FDA “commonly relied on facilities to voluntarily correct [the] . . . violations” in response to a Warning Letter, Untitled Letter or similar action by FDA. According to OIG, FDA actions were “not always timely.” In the period from 2011 to 2015, FDA took 1,113 “advisory actions” consisting of 903 warning letters, 136 regulatory meetings, and 74 “untitled letters.” Those actions were taken (on average) 4.4 (warning letters and meetings) to 6.1 months (untitled letters) after an inspection.

OIG further determined that in the five-year period, FDA ordered a suspension of a food facility twice (0.8 months after the inspection) and five administrative detention orders (0.2 months after the inspection). FDA sought judicial action 58 times, and won seizure orders in 21 instances. OIG noted that FDA did not use its mandatory recall authority. Of course mandatory recall is not needed if companies recall products when asked by FDA.

For almost 50% of the OAI inspections, FDA did not conduct a follow-up inspection within 1 year and for 17% of the OAI inspections, FDA did not conduct a follow-up inspection of the facility at all. In cases that FDA did a reinspection, one in five facilities received a second OAI classification. Three quarters of these second OAI classifications involved the same problem that caused the first OAI classification.

OIG recommend that FDA:

1. improve how it handles attempted inspections to ensure better use of resources;
2. take appropriate action against all facilities with significant inspection violations;
3. improve the timeliness of actions, including warning letters; and
4. conduct timely follow-up inspections to ensure that significant inspection violations are corrected.

FDA’s written responses and explanations are in the OIG report. FDA generally concurs with the OIG recommendations.

A major goal of FSMA is to be preventive rather than reactive. During the five-year period studied by OIG, the majority of food facilities were not yet subject to the preventive control regulations. It will be interesting to see how the implementation of these requirements affects FDA inspections and compliance.

In July of last year, FDA released a draft guidance on evaluation and reporting of age-, race-, and ethnicity-specific data in medical device clinical studies (see our post on the draft guidance here). On September 12, 2017, FDA released the final version of this guidance.

The stated objectives of the guidance are to:

1. Encourage the collection and consideration during the study design stage of relevant age, race, ethnicity, and associated covariates for devices for which safety, effectiveness, or benefit-risk profile is expected to vary across these groups;
2. Outline recommended analyses of study subgroup data, with a framework for considering demographic data when interpreting overall study outcomes; and
3. Specify FDA’s expectations for reporting age-, race-, and ethnicity-specific information in summaries and labeling for approved or cleared medical devices.

This guidance is intended to extend and complement two earlier guidance documents on sex, race, and ethnicity data: Evaluation of Sex-Specific Data in Medical Device Clinical Studies (Dec. 2011) and Collection of Race and Ethnicity Data in Clinical Trials (Sept. 2005).

The guidance emphasizes that when “clinically relevant differences in treatment effect are anticipated across age, racial, or ethnic groups,” sponsors should consider proper clinical study design, proper enrollment of subgroups, and control of study-wise Type 1 error for overall and subgroup-specific hypothesis testing.” To that end, the guidance outlines specific recommendations for achieving appropriate enrollment; considering age, race, and ethnicity in study design, analysis, and interpretation of study results; and submitting age-, race-, and ethnicity-specific data in submissions to FDA and reporting in public documents.

The content of the final guidance document is largely unchanged compared to the draft guidance (outlined in detail in our previous post here). However, FDA was very responsive to suggested revisions from industry and other non-profit groups submitted to the Agency in comments on the proposed draft guidance.

The Association of American Medical Colleges (AAMC) suggested additions to the guidance’s section on study design and the early enrollment stage. In particular, they suggested additional recommendations to enhance enrollment of relevant age, racial, and ethnic subgroups, such as creating materials appropriate for low-literacy populations, utilizing communication through electronic means and social media, and working with minority health professional organizations and patient advocacy groups. FDA incorporated all of these suggestions for enhanced enrollment strategies.

The Advanced Medical Technology Association (AdvaMed) made several specific suggestions, which FDA incorporated in the final guidance. For example, AdvaMed suggested that FDA delete a subsection titled “Special Study Design Considerations for Diagnostic Devices” because “[i]t is unclear why special study design considerations would only apply to diagnostic devices.” FDA took AdvaMed’s advice, and this subsection does not appear in the final guidance. Additionally, AdvaMed suggested that FDA state that hypotheses for exploratory (i.e., post-hoc) analyses should be consistent with the literature of the natural history of the disease and its prevalence in subgroups or be consistent with the known pathophysiology. The final guidance includes this statement in a section on interpretation of age-, race-, and ethnicity-specific data.

The 510(k) Coalition, which is a coalition of medical device companies, stated in its comment on the draft guidance that it would like clarification on whether a company should submit modified labeling if it determines post-clearance or approval that there are clinically meaningful age-, race-, and/or ethnicity-specific differences in disease course, outcomes, or benefit-risk profile. FDA added a statement to the guidance encouraging the use of postmarket data to “modify labeling to support additional information regarding device safety or effectiveness and/or to clarify how the device should be used.”

MED-EL, a manufacturer of implantable hearing systems, pointed out that FDA used an outdated example in its discussion of why it is important to consider age-specific differences. In the draft guidance, FDA stated that the use of cochlear implants in certain pediatric subgroups may not be advisable due to the size of the implant or may be inappropriate due to the stage of neurological development of the child. MED-EL explained in its comment that the cochlear implants it manufactures are indicated for patients one year of age or older. As a result, FDA did not include this example in the final guidance.

At least two groups (AAMC and Bridge Clinical Research) stated in their comments on the draft guidance that FDA should use stronger language in the guidance or promulgate regulations regarding increased diversity in clinical trials. For example, AAMC recommended that FDA suggest all studies consider collection of age, race, and ethnicity data, not solely those for which subgroup differences are anticipated. FDA did not appear to revise the guidance to include stronger language or suggest the possibility of future rulemaking on this topic. The requested expansion by AAMC could have presented a significant burden for devices in which there is no potential for differences in age, race, and ethnicity.

Two groups, the Patient, Consumer, and Public Health Coalition and the National Women’s Health Network recommended that FDA create an equivalent program to FDA’s “Drug Trials Snapshots” program for devices. FDA’s Drug Trials Snapshots summarize information about the demographics of people who participate in drug clinical trials and highlight whether there were any differences in benefits and side effects among sex, race, and age groups. FDA did not mention the possibility of creating a similar program for devices in the final guidance, but it will be interesting to see whether FDA makes device clinical trial demographic information available to the public in the future as a way to encourage compliance with the guidance. Certainly on the diagnostic side, we may see FDA expressly include this type of information in its decision summaries posted on FDA’s website.

* McKenzie E. Cato is a Law Clerk

Pushing forward with his commitment to accessibility, Commissioner Gottlieb recently announced further efforts to encourage generic approval. In another FDA Voice Blog Post, Dr. Gottlieb reiterated the agency’s renewed focus on drug pricing and competition and announced new measures to aid in the development of generic versions of “complex drugs.”

Complex drugs, like drug-device combinations or injectable drugs or other forms of complex active ingredients or sites of action, are generally high-cost medicines that are not frequent targets of generic development regardless of patent or exclusivity status. These drugs are often difficult to replicate and have murkier pathways to approval; demonstrating bioequivalence may be challenging when the active ingredient cannot be easily measured in the blood or the therapeutic effect is not delivered systemically. This complexity delays and deters generic development, allowing NDA holders to charge a premium for the brand version.

In an effort to assist potential ANDA applicants for complex products, FDA issued a new draft guidance this week providing information to help sponsors request and conduct product development meetings, pre-submission meetings, and mid-cycle review meetings – all of these are commitments that FDA agreed to in the GDUFA II negotiations. These tools are similar to those available for NDAs under PDUFA, and the initiative is intended to enhance communication between generic drug applicants and FDA early in the development process to allow for more efficient development, review, and approval.

FDA issued an additional draft guidance this week to assist applicants submitting an ANDA for synthetic peptide drug product referring to an rDNA peptide – specifically glucagon, liraglutide, nesiritide, teriparatide, and teduglutide. According to this guidance, FDA believes that peptide synthesis and characterization technology now allows an ANDA applicant to demonstrate that the active ingredient in a generic synthetic peptide drug product is the “same” as the active ingredient in an rDNA peptide based largely on impurity profile comparisons. Because there are quite a few branded medicines without exclusivity that are peptides (compounds made up of 40 or fewer amino acids), this guidance could allow new competition where previously no generic development existed.

FDA is taking advantage of scientific development to expedite drug access and competition. As part of this initiative, Dr. Gottlieb states that FDA’s generic drug regulatory science program will work to develop more tools, methods, and efficient alternatives to clinical endpoint testing in the next year to further enable competition. FDA will continue to hold scientific workshops identifying opportunities for development for both product-specific guidance documents and new analytical tools.

This FDA Voice post is yet another in a series emphasizing FDA’s push towards affordable access to medicines. The enthusiasm with which this administration is addressing drug pricing and competition is not surprising, given Dr. Gottlieb’s extensive economic and health policy background, but it is certainly untraditional with respect to the role FDA has traditionally played in drug pricing. It’s certainly interesting to watch the agency’s “public health” mission expanding in front of our eyes, and we’re looking forward to seeing what else is in the pipeline!

Occasionally we peruse FDA’s inventory of food and color additive petitions under review as a reminder of what might lie on the horizon.  The current list includes some that have gotten considerable attention, and others that have largely flown below radar.  Among the latter, one stands out for its potential to offer a reminder of the nettlesome nature of the Delaney Clause.

By way of background, the Delaney Clause is a provision in the FFDCA that prohibits FDA from approving a food additive if it is found to induce cancer in man or animal, and is so named after the legislator who insisted on its inclusion in amendments to the FFDCA (there actually is more than one such provision in the FFDCA, but that’s beyond the scope of this posting.)  Attacked from the beginning as an unscientific approach to the complex challenge of assessing potential carcinogenicity, the Clause has spawned literally decades of litigation as the agency worked to administer it in light of our advancing scientific understanding of the disease – or rather suite of diseases – that it was intended to address.

One of the food additive petitions under review invokes the Delaney Clause to ask that FDA amend its food additive regulations to disallow the use of seven synthetic flavoring substances, and to prohibit their use.  The petition contends that the substances have been found to induce cancer in man or animal by the National Toxicology Program of the U.S. Department of Health and Human Services, as well as the California Environmental Protection Agency’s Office of Environmental Health Assessment (the office that administers Proposition 65).  Submitted by a coalition of consumer advocates and filed on January 4, 2016, the petition is getting long in the tooth.  The FFDCA establishes a 6-month timeframe for the review of food additive petitions.  Although extensions are the norm, recent history has shown that consumer advocates are disinclined to wait indefinitely for agency action.  Thus, as the 2-year anniversary approaches for this petition, it’s reasonable to expect movement either in the form of a substantive response by the agency, or a lawsuit to compel action.

If indeed the substances in question are found to induce cancer in man or animal within the meaning of the Delaney Clause, then FDA’s hands may be tied – regardless of whether the currently approved uses of the substances meet the safety standard otherwise applicable to food additives (reasonable certainty of no harm).  The resulting revocation of food additive approval could call into question the regulatory status of any foods to which those substances have been added.  Further, it could prompt additional petitions seeking similar action with respect to other substances for which there is evidence of human or animal carcinogenicity.  Ultimately, the only fix might lie in a statutory amendment that would – once and for all – bring the FFDCA’s approach to potential carcinogens in line with contemporary scientific understanding.  Anyone want to take odds on that outcome?

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks an attorney to work with our drug development team. The attorney will assist our clients secure FDA approval for new drugs by leveraging our legal expertise of the approval standards in the FDC Act and implementing regulations to overcome potential regulatory or scientific impediments. The position affords the opportunity to participate in product development strategy at the initiation stage and to navigate the drug through the FDA regulatory process.   

Strong verbal and writing skills are required, as well as a detailed understanding of FDA and the regulatory process.  Ideal candidates will possess a scientific background, such as a masters degree or higher in a hard science.  

Late last month, Judge Wolf, in the federal district court for the district of Massachusetts, dismissed a putative class action against a number of defendants based on impossibility preemption.  The plaintiffs’ basic allegations were that the defendants, all of which manufactured or distributed prescription eye drops, had dispensers that “were intentionally designed to dispense more liquid than the human eye is capable of absorbing.” Plaintiffs further alleged that the purpose of this unfair practice was to cause consumers to purchase more of their product than necessary thereby increasing defendants’ profits.  Before getting to its analysis, the court’s opinion summarized recent Supreme Court decisions – Wyeth v. Levine (failure to warn claims against brand manufacturer not preempted under impossibility preemption because of FDA’s changes being effected (CBE) regulation); Pliva v. Mensing (failure to warn claims preempted because generic manufacturers cannot use CBE regulation); and Mutual Pharm. v. Bartlett (option to stop selling product does not avoid impossibility preemption).

Against that backdrop, the court reasoned that plaintiffs’ claims were preempted because “defendants here could not have marketed droppers that complied with state consumer protection and unjust enrichment laws in the manner plaintiffs advocate without the FDA’s prior approval.”  Central to the court’s analysis were two FDA guidance documents that classified as major changes—and therefore changes that could not be made under the CBE regulation—any changes to the size and shape of the container for sterile drug products such as eye drops.  Based on these guidance documents, the court reasoned that it was impossible under federal law for the defendants to make the changes that plaintiffs alleged were necessary under state law.

The court, while recognizing a split in authority, was unpersuaded by the argument that plaintiffs’ claims were not preempted because defendants could have designed their products differently prior to FDA approval.  The court did not reach several arguments raised by the defendants, including but not limited to a separate motion by generic defendants based on the Supreme Court’s analysis of the availability of CBE to generic manufacturers

Earlier this year, a front page story in the Washington Post spotlighted several cases of fraudulent organic certificates, raising questions about organic certification practices overseas. Now, a new report by USDA’s Inspector General (IG) report confirms those doubts.

The IG reviewed the process used by the National Organic Program (NOP) of the Agricultural Marketing Service (AMS) to determine equivalence of organic standards used by countries exporting to the United States and compliance of imported products with NOP organic standard. Based on its audit, the IG makes a total of nine recommendations for improvements in four different areas.  In summary, the IG found 1) A lack of transparency of the equivalency determination; 2) A lack of verification of documents of imported organic products from countries that have been determined to have an equivalent system (certificates have been required since 2012 but are not verified); 3) Inadequate control over fumigation of imported organic products at the port (fumigation is inconsistent with organic standards); and 4) Infrequent (not timely) audits of foreign countries’ procedures.

AMS responded to the IG report with agreement and a commitment to carry out the IG’s recommendations. AMS already executed a memorandum of understanding with the Animal Plant Health Inspection Service (APHIS) earlier this year to address communication and notification procedures between the two about fumigation of imported shipments.  For the remaining recommendations, AMS committed to addressing them by July 2018.

The IG report makes no mention of the Washington Post article, or Cornucopia’s subsequent petition to the National Organic Standard Board (NOSB) requesting several actions to strengthen NOP’s control of import of organic product.

We have witnessed this past week some noteworthy activity in the drug compounding space. Where will this lead traditional compounders and outsourcing facilities? What will it mean for compounders in the months ahead?  We will just have to wait until FDA releases anticipated draft guidance on changes in outsourcing facility compounding in the coming months. FDA’s announcement about draft outsourcing guidance is somewhat of a headscratcher, especially considering that a number of anticipated compounding guidance documents and regulations were recently moved to CDER’s regulatory agenda inactive list (here; search “drug”).

Curiosity notwithstanding, Commissioner Gottlieb published a statement on September 26, 2017, addressing FDA’s “new efforts to encourage compounding of better quality drugs” under the Drug Quality and Security Act (DQSA), and provide increased access to compounded medications from outsourcing facilities.  First discussing the need for compounded medications, the Commissioner states,  “Supporting access to compounded drugs made under high production standards involves helping new outsourcing facilities as they strive to develop expertise in compounding medicines under [cGMP] standards.”  Dr. Gottlieb further notes the Agency is committed to “realizing” DQSA’s framework for facilities that register as outsourcing facilities;” thus, FDA is working on a number of efforts “specific to this growing sector as to works to meet these regulatory standards and fulfill its intended role.”

Interestingly, the “growing sector” (based on FDA’s website listing of such facilities) shows that, notwithstanding the four years since the DQSA’s enactment, there are only about 72 outsourcing facilities:  FDA has issued Form 483s to all but a few of them, Warning Letters to dozens of them, and engaged in recall activities and shutdowns of many.   Around 40 outsourcing facilities have closed their doors since their much anticipated opening after the enactment of the DQSA four years ago.

Nevertheless, Commissioner Gottlieb’s statement shares a Guide, titled “Outsourcing Facility Information,” which he claims may “assist compounders in deciding whether to become outsourcing facilities.,”  FDA’s Outsourcing Facility Information Guide is a very  general and well-organized  primer on Section 503B compounding.  It describes in chart form the various requirements in Section 503B, and informs the reader whether there is draft or final guidance, or anticipated guidance or regulations concerning each requirement.  The Guide  also provides handy links to the various guidance documents that FDA has promulgated addressing compounding under Section 503B over the last four years.

In its attempt to make the outsourcing registration decision as “efficient as possible, FDA’s Guide is “one step in [FDA’s] efforts help more pharmacies become outsourcing facilities.  Although we don’t yet know what else FDA intends to do to create these “efficiencies,” Dr. Gottlieb states that FDA will “continue to streamline” the process and “appropriately calibrate the regulatory burden” of operating as an outsourcing facility.  The Commissioner concludes: “Our ultimate  goal is to make it more feasible”  for compounding pharmacies to register to become outsourcing facilities, enabling them to grow their business under a legally approved framework, and increase access to better quality compounded drugs….”

Although not once referenced in the Commissioner’s statement, compounds prepared under the statutory rubric set forth in Section 503A (for individually identified patients pursuant to a prescription or order) are indeed another “legally approved framework” for compounded medications, and there are thousands of such compliant pharmacies operating throughout the United States.

As further demonstration to FDA’s commitment to safe compounding, FDA also met with state partners as part of is sixth intergovernmental meeting on drug compounding. This is part of the Agency’s continuing  effort to provide more seamless coordination between states and FDA in the regulation of compounding.   The press release about the meeting addresses targeting oversight by both FDA and states due to limited resources.  Noting the varied types of pharmacies across the country – from “mom and pop” pharmacies to those that ship nationwide like conventional drug manufacturers-  FDA and states will collaborate to determine which ones should be overseen primarily by states, and the small number of larger pharmacies deserving of FDA oversight.  Along these lines, FDA states that it intends to “further enhance our risk-based inspection model to prioritize inspections of compounding pharmacies that operate on a larger scale and ship compounded drugs across multiple state lines.”  Thus large volume traditional compounders should consider themselves warned: FDA is paying attention to compounders that ship a lot of product at high volumes across state lines.  There is nothing in the press release, however, that discusses the efforts, if any (and unlike reported from other meetings ) to ease the confusing and disparate licensing requirements facing FDA- registered outsourcing facilities .  Hopefully creating this “efficiency” is on FDA’s immediate “to do” list

Lastly, FDA published a report, available for your perusal via a link in Dr. Gottlieb’s statement above, setting forth a list of drugs that outsourcing facilities have produced.  Note that outsourcing facilities, unlike traditional Section503A compounders, must report to FDA drugs compounded in June and December of each year.  The list is a spreadsheet 500 pages long that only includes drugs produced (for those facilities that reported) for the time period between December 2016 and May 2017, including the name of the facility, active ingredient information, package description (and dosage amount), and dosage form.

We will keep you posted on outsourcing facility and compounding developments.

On September 26, 2017, FDA combined and finalized two Draft Guidance documents first issued in 2011 that set forth the Agency’s approach to classifying products as “drugs” or “devices” under the FDC Act § 201. In doing so, FDA trimmed significant portions of both Draft Guidance documents ostensibly “for clarity and ease of reference.” See Classification of Products as Drugs and Devices and Additional Product Classification Issues; Guidance for Industry and Food and Drug Administration Staff; Availability, 82 Fed. Reg. 44,802, 44,803 (Sept. 26, 2017).  However, while the Final Guidance does provide helpful clarification and examples, some of the most significant issues with the Draft Guidance documents persist.

The Draft Guidance documents issued in 2011 (which can be found here and here) were titled “Classification of Products as Drugs and Devices & Additional Product Classification Issues,” and “Interpretation of the Term ‘Chemical Action’ in the Definition of Device under Section 201(h) of the Federal Food, Drug, and Cosmetic Act” (hereinafter “Draft Classification Guidance” and “Draft Chemical Action Guidance,” respectively).  These documents were met in 2011 with numerous objections from the medical device industry, because the Agency’s position significantly diminished the scope of the “device” definition.

Specifically, FDA’s Draft Classification Guidance stated that (1) any therapeutic effect by a product would be considered a “primary intended purpose” pursuant to FDC Act § 201(h), and (2) if a product that depends “even in part” on chemical action within or on the body to achieve a primary intended purpose, it is excluded from the device definition. See Draft Classification Guidance at 5.  The Agency further clarified that no chemical action with therapeutic effect would be permitted in a device, noting that “a product that exhibits chemical action within or on the body of man” could remain within the device definition only if its chemical action contributes to something other than a primary intended purpose (i.e., therapeutic effect). Id. at 4-5.

Moreover, the Draft Classification Guidance acknowledged that the new positions set out in both Draft Guidance documents may result in the FDA Office of Combination Products (OCP) changing its view of products that the Agency had already classified, stating that OCP “may determine that, in light of current scientific understanding, the means by which such a [previously classified product] or constituent part achieves an intended use may warrant a different classification for that product or constituent part in the pending RFD than the Agency previously provided.” Id. at 6.

FDA was challenged in litigation over the Agency’s reliance on the extra-statutory “even in part” standard not found in the FDC Act’s definition of “device,” its seeming prohibition of even de minimus chemical action contributing to a therapeutic effect, and its unexplained departure from prior precedents.  The Agency lost at least two lawsuits over its new interpretation of “device.”

In concession to industry concerns, the Final Guidance’s discussion of “chemical action” makes clear that chemical action occurring within the body, but which does not interact “at the molecular level with bodily components . . . to mediate (including promoting or inhibiting) a bodily response, or with foreign entities (e.g. organisms or chemicals) so as to alter that entity’s interaction with the body,” is not sufficient to render a product a drug for purposes of FDA regulation. Final Guidance at 7.  FDA further clarifies that while “interaction at the molecular level” could include chemical reaction, intermolecular forces (e.g. electrostatic interactions), or both, “[t]he mere exchange of non-chemical energy (e.g., electromagnetic or thermal energy) between a product and the body would not constitute ‘chemical action.’” Id. at 7 n. 12.

For example, FDA notes that a polymethlymethacrylate (PMMA) bone spacer would still be considered a device, even though “the molecules [within the product] interact with each other to create a solid mass to fill a bone void physically,” because that “process does not require an interaction between the PMMA and the bone at the molecular level . . . .” Id. at 9 (emphasis supplied).  And topical surgical adhesives, despite bonding to a cut/incision, do not exhibit chemical action “because that binding does not mediate a bodily response.” Id.

At the same time, FDA continues to take the position that the FDC Act’s “drug” definition subsumes the more restrictive “device” definition (Id. at 5), and that product sponsors bear the burden of proving that their product is correctly classified as a device (or drug, as the case may be) (Id. at 6).  Given the difficulty of proving the absence of biological and chemical effect, this burden shifting gives FDA ample room to make mischief.  Moreover, while the Final Guidance no longer states outright that the Agency considers every therapeutic effect to be a primary intended purpose, the examples it cites of products that exhibit chemical action in or on the body, but that remain “devices,” include only products whose chemical action otherwise meets FDA’s definition, but does not contribute at all to a therapeutic purpose of the device.  There is no indication in the Final Guidance that FDA would accept as a device a product exhibiting even minimal chemical action that contributes to a therapeutic effect.  Finally, while FDA states that it has “reconsidered inclusion of content on the status of prior Agency classification decisions” in the Final Guidance, the Agency makes clear that product sponsors should not rely on classification precedents without confirmation by OCP that those precedents remain valid.  82 Fed. Reg. at 44,803.

In sum, while FDA has taken steps toward providing greater certainty to product sponsors by clarifying its stance on the meaning of “chemical action” in this Final Guidance, the Agency’s positions on the remainder of the statutory “device” definition, and on the sponsor’s burden of proof to establish product classification, continue to heavily favor a “drug” designation for hard-to-classify products. This result is arguably contrary to the statutory text, and – in light of the significantly higher cost associated with seeking premarket approval for a drug product – is very likely to result in fewer beneficial therapeutic products reaching the U.S. market.