Device Firms: What You Should Know About The 21st Century Cures Act

By Mason Weeda

Last month, legislation that would affect, among other things, FDA’s regulation of medical devices and the manufacturers of such devices took a considerable step forward when it was introduced and then unanimously approved by the House Energy and Commerce Committee by a vote of 51-0 on May 21.  Known as the 21st Century Cures Act (“Act”), the stated aim of the legislation is to modernize and personalize health care, encourage innovation, support research, and streamline the U.S. health care system to promote the delivery of better and faster “cures” to more patients.

In support of this goal, the Act would change the review of medical devices determined to be “breakthrough,” establish a third-party option for the inspection of medical device manufacturers, make changes to certain Humanitarian Device Exemption (“HDE“) requirements, institutionalize FDA’s ongoing efforts regarding the regulation of medical software applications, and loosen some clinical investigation requirements.  Significantly, the legislation also indicates an ongoing Congressional interest in the restrictions FDA has placed on the dissemination of truthful and nonmisleading off-label information.

Breakthrough Device Pathway

The Act would support faster “cures” by creating a “priority review” pathway for those devices that meet the definition of a “breakthrough device.”  These “breakthrough devices” include those that “represent breakthrough technologies… for which no approved alternative exist,” offer “significant advantages over existing approved or cleared alternative,” and are “otherwise in the best interest of patients.”

Upon a sponsor’s request, FDA would determine whether a device meets the “breakthrough device” designation using specified criteria.  If a device receives such designation, it would be eligible for expedited review by a team of staff that will interact with the device sponsor.  During this process, the Act would require FDA to “take steps to ensure that the design of clinical trials is as efficient as practicable, such as through adoption of shorter or smaller clinical trials, application of surrogate endpoints and use of adaptive trial designs and Bayesian statistics.”  Likewise, the agency would also be required to “facilitate … expedited and efficient development and review of the device through utilization of postmarket data collection.” Although these are laudable goals, the Act does not impose any specific timelines in which an “expedited review” must be completed or otherwise quantify how much existing review times will be reduced.

Third-Party Inspections of Device Manufacturers

The Act also contains provisions that could allow FDA to conserve its inspectional assets and speed up approval of modified versions of existing devices by allowing for the use of third party inspectors to conduct the necessary establishment inspections.  The theory being that creating a “quick” method to inspect facilities in these circumstances would promote the earlier availability of improved “cures.”

Under the provisions of the Act titled “Medical Device Regulatory Process Improvements,” Congress would require FDA to establish a “third-party quality system assessment” program, where accredited third parties would inspect manufacturers for compliance with the Quality System Regulation (“QSR”) (21 C.F.R. Part 820).  However, use of such third-party inspections would be limited only to QSR inspections necessary as the result of submissions involving “device related changes” and would not be available in other types of establishment inspections.

Changes to Humanitarian Device Exemptions

This section of the Act would double the number of patients that must suffer from a disease in order for FDA to consider it a “rare disease.”    Presently, the HDE pathway is intended to incentivize and encourage the development of devices to treat “rare” diseases or conditions affecting small patient populations when the device manufacturer`s research and development costs would otherwise exceed its market returns.  It does so by significantly reducing the clinical data that would be necessary for the manufacturer to generate to support the efficacy of the device that would otherwise be required by FDA in a traditional marketing application. To qualify for an HDE, the disease or condition must presently affect fewer than 4,000 individuals in the United States per year. The Act seeks to encourage additional development making “cures” more widely available by increasing this number to 8,000 individuals.

Medical Software

In an apparent effort to “modernize” the technology involved in health care, the Act would create a definition of “health software,” which generally would not be regulated unless it:

  • is intended for use to analyze information to provide patient-specific recommended options; or
  • FDA determines that it poses a significant risk to patient safety.

This provision continues to allow FDA some flexibility as to how it may regulate software.  The Act also would require the agency to review existing regulations and guidance regarding software, including the classification of software, standards of verification and validation, review of software, and quality system for software, among others.

Clinical Trials

The Act would also make it easier for sponsors conducting clinical investigations by requiring the Department of Health and Human Services (“HHS”) to harmonize its requirements applicable to clinical investigations with FDA’s own requirements. This supports the Act’s goals by significantly reducing the regulatory burden imposed on sponsors who must presently ensure that their clinical investigations meet the often duplicitous requirements imposed by both HHS and FDA controls.  The Act also would make it easier for sponsors to meet Institutional Review Board (“IRB”) requirements by allowing the use of non-local IRBs to review medical device trials, including Investigational Device Exemptions (“IDE”) and HDEs. Permitting the use of non-local IRBs support the Act’s goal of “quicker cures” by eliminating the “log jam” and delays sometimes associated with the use (and overuse) of local IRBs by giving sponsors additional options that are potentially faster than the traditional ones.

Promotion

Lastly, and without limitation, the Act’s section on “Facilitating Responsible Communication of Scientific and Medical Developments,” provides that FDA “shall, within 18 months, issue draft guidance on facilitating the responsible dissemination of truthful and non-misleading scientific and medical information not included in the approved labeling of drugs and devices.”  This provision appears to be in response to the Coronia Case (U.S. v. Caronia, 703 F.3d 149 (2d Cir. 2012)), which holds that representatives of pharmaceutical manufacturers have a right under the First Amendment to make truthful statements regarding their products, even if such statements indirectly promote drugs for uses not approved by FDA.  The Act does not provide further direction on this topic, but Congress is clearly nudging FDA to update its position on off-label promotion which may affect medical device manufacturers.

It may be an uphill battle for Congress to agree on all topics involved in the 308 pages of 21st Century Cures Act.  However, as reported by the House Energy and Commerce Committee Press Releases, the bill appears to have support from industry and consumer groups, which may help bring Congress together.

John Block: GMOs Under Assault

By John R. Block

We can’t seem to silence or satisfy the loud scream of opposition to GE crops. The reason probably is that up until now we have ignored them. It’s time to stand up and set the record straight.

GE food is safe and even beneficial according to 88% of scientists. We have conducted more than 1,000 studies. We have been eating GE food for more than 20 years – no one has gotten sick.

The fact is that for thousands of years, farmers have been improving crops through selective breeding. That process alters genes. We have found that in the laboratory we can do it faster.

Never mind the facts, the critics are beating the drums. Three states have passed labeling laws. Vermont is in the lead as they begin to implement their law. It sounds simple. Just label the food if it has GMO products in the food.

It’s not that simple. Vermont has a long list of exemptions. Animal products are exempt – beef, pork, chicken, dairy. But keep in mind the animals were fed GMO corn and soybean meal.

Trying to get out ahead of everyone, Chipotle recently announced that it has gone GMO free. But it’s not really free. The soft drinks are made with GMO corn sweetener. The burritos have GMO corn-fed beef, pork, chicken, and GMO sour cream.

The U.S. Congress is considering as many as 30 bills to deal with the GMO debate. You may wonder where all of this noise is coming from. Yes, there are individuals that sincerely are concerned about GMO safety. However, the organic companies (some of them are huge) are helping to push the false argument about risk. If they succeed, they can sell more product and make more money.

This debate is not over. You will soon read about the next step in plant technology – gene editing. Gene editing is a more precise way to alter plant traits.

The leading critics of GMOs are totally inconsistent. First, they support the science on global warming, but ignore the science on GMOs. Next, they pretend to care about the poor, but genetic engineering helps the poor by keeping the cost of food down. The world will not produce enough food without new technology. Finally, if they want to reduce the use of chemicals and energy, GE also does that.

Stay tuned.

John Block was Secretary of the U.S. Department of Agriculture from 1981-1985, where he played a key role in the development of the 1985 Farm Bill.

FDA Releases Draft Guidance on Compounding Animal Drugs

By Tish Eggleston Pahl

Yesterday, FDA released a Draft Guidance for Industry on Compounding Animal Drugs from Bulk Drug Substances (Draft Guidance).  The Federal Register notice accompanying the Draft Guidance can be found here.  The agency also withdrew its previous Compliance Policy Guide (CPG) 608.400, Compounding of Drugs for Use in Animals.

Though FDA has been actively implementing Title I of the Drug Quality and Security Act (DQSA) and exercising its new, clearer authority over outsourcing facilities and compounding pharmacies, the new §503B and amended §503A of the FD&C Act do not apply to the compounding of animal drugs. Arising from FDA’s recent, vigorous oversight of compounding pharmacies and outsourcing facilities, the Draft Guidance reflects the agency’s current, and more sophisticated, thinking about compounding.

The Draft Guidance describes the conditions under which FDA does not intend to initiate enforcement action against State-licensed pharmacies, licensed veterinarians, and facilities registered as outsourcing facilities under §503B of the FD&C Act that compound animal drugs from bulk drug substances. Outsourcing facilities are new entities created under the DQSA that, if they follow cGMPs and other requirements, are permitted to compound sterile injectable drugs for humans without FDA pre-approving an application under §505 and without the “adequate directions for use” required by §502(f)(1).  The Draft Guidance sets out pre-conditions for the exercise of enforcement discretion for each type of entity – State-licensed pharmacies, licensed veterinarians, and outsourcing facilities.  Unlike pharmacies and veterinarians, outsourcing facilities will only be permitted to compound from bulk substances identified in the to-be-developed Appendix A.

FDA separately seeks comments on the list of acceptable bulk substances to add to the Appendix A list.  The agency also asks for comments on various other issues, including:

  • The significance of drug shortages to animal drug compounding;
  • The appropriate standards for compounding by licensed veterinarians;
  • Possible limitations on total drugs to be compounded and whether they may be transferred or sold to others; and
  • Whether the agency needs to address repackaging of animal drugs, as it did for human drugs.

For compounders of animal drugs, these are significant documents that warrant close inspection.  FDA will be accepting comments for 90 days.

Clearing Up Confusion: The Net Quantity of Contents Declaration on Food Labels

By Robert A. Hahn

The FDA’s food labeling regulations include some traps for the unwary.  A few of those traps have to do with the net quantity of contents declaration.

Here are a couple of points to keep in mind when declaring a food product’s net contents:

  • When the net contents declaration is expressed in terms of weight, FDA requires that the declaration include the words “Net weight” or the abbreviation “Net Wt.” However, when the net contents is expressed in fluid measure or numerical count, use of the words “Net” or “Net Contents” is optional.  21 C.F.R. § 101.105(j)(3), (n).  NOTE: In 1993, FDA proposed to remove the requirement to include the words “Net Weight” or “Net Wt,” but the proposed rule was withdrawn in 2004.  See 58 Fed. Reg. 29716, 29724 (May 21, 1993) and 69 Fed. Reg. 68831 (Nov. 26, 2004).  FDA’s current position is that the prefatory language “Net weight” or “Net Wt” is required when the net contents is expressed in terms of weight.  The abbreviation “Net Wt” is frequently presented in all upper case letters, e., “NET WT.”
  • Although FDA regulations continue to provide that a separate statement of the net contents in metric measure is optional (21 C.F.R. § 101.105(p)), the fact is that the net contents declaration, with very limited exceptions for random weight packages and for foods packaged in a retail store, must be expressed in both avoirdupois measure (g., ounce, pound, fluid ounce, pint, quart) and metric measure (e.g., milligram, gram, milliliter, liter). The Fair Packaging and Labeling Act (FPLA) was amended in 1992 to require use of metric measure (15 U.S.C. § 1453(a)(2)), but FDA has never amended its regulations to implement this statutory change.  Nevertheless, the FPLA is the law.
  • FDA requires that the net contents declaration use the largest appropriate unit of measure.  For example, 24 oz should be expressed as “1.5 lb,” “1 ½ lb,” or “1 lb 8 oz,” and 1,100 mL should be expressed as “1.1 L.”  Again, the FPLA was amended to require use of the largest appropriate unit of measure, but FDA has not amended its own regulations to reflect the statutory change.  NOTE: “Dual avoirdupois” declaration (i.e., expressing the net contents in avoirdupois measure using both the largest appropriate unit of measure and ounces or fluid ounces, as, for example, “1.5 lb (24 oz) 680 g”) is permitted as an option to facilitate value comparisons by consumers.

Recapping Round 1 of the Vermont GMO-Labeling Lawsuit

By John G. Dillard

Millions across the globe tuned into this weekend’s Mayweather-Pacquiao bout, which was billed as “the fight of the century.” However, the pay-per-view event was not the only high stakes fight to report on from last week. Far away from the glitz and glamor of Las Vegas, a federal court in Vermont issued a much-anticipated opinion in what will be one of the true fights of the century for the American food industry – whether state governments can mandate GMO labels.

On April 27, 2015, Chief Judge Christina Reiss of the U.S. District Court for the District of Vermont issued an opinion that mostly favored the State of Vermont and the positions of GMO-labeling advocates. In the case, Grocery Manufacturers Association v. Sorrell (No. 5:14-cv-117), the Grocery Manufacturers Association, Snack Food Association, International Dairy Foods Association, and National Association of Manufacturers (the “Plaintiffs”) are challenging Vermont’s Act 120, which requires that certain foods sold at retail stores in Vermont bear mandatory labeling if they contain genetically-engineered ingredients. Act 120 also prohibits manufacturers from advertising or labeling foods that contain genetically-engineered ingredients as “natural” or “all natural.”

Both supporters and opponents of mandatory GMO-labeling have been keeping a close eye on this lawsuit. This is because Act 120, if it survives litigation, will make Vermont the first state in the country to require that certain foods containing ingredients produced with genetic engineering bear mandatory labels. GMA v. Sorrell is the test case for this issue, which will certainly reach the Second Circuit Court of Appeals and, possibly, the Supreme Court.

The Plaintiffs challenged Act 120 from several angles. First, the Plaintiffs asserted that Act 120’s GMO-labeling mandate was unconstitutional under both the First Amendment and the Constitution’s Commerce Clause. The Plaintiffs also argued that the GMO-labeling mandate was preempted by the Federal Food, Drug, and Cosmetic Act (FFDCA), the Nutritional Labeling and Education Act (NLEA), the Federal Meat Inspection Act (FMIA), and the Poultry Products Inspection Act (PPIA). Furthermore, the Plaintiffs asserted that the ban on “natural” labeling is unconstitutional under the Commerce Clause and the First Amendment.

The State of Vermont filed a motion to dismiss the Plaintiffs’ case on August 8, 2014. Subsequently, the Plaintiffs sought a preliminary injunction that would halt implementation of Act 120 while the Court decides whether to issue a permanent injunction invalidating Act 120. Chief Judge Reiss heard oral arguments on both of these motions on January 7, 2015, and issued an 84-page opinion in the case last Monday.

GMO-Labeling Mandate

The Plaintiffs challenged Act 120’s GMO-labeling mandate under the First Amendment, Commerce Clause, and Supremacy Clause. Here is how the Court addressed these issues:

  • First Amendment. The Plaintiffs alleged that Act 120’s GMO-labeling mandate violated the First Amendment’s protections against unlawfully-compelled speech. The Court held that “strict scrutiny” was not warranted in this case and dismissed the Plaintiffs’ complaint to the extent that it argued strict scrutiny applied. Instead, the Court held that the proper standard is most likely the “reasonable relationship” test. Under this test, also known as the Zauderer test, the Court held that for the purposes of preliminary injunction, the Plaintiffs were not likely to succeed on their First Amendment complaints. The Court reasoned that unless Vermont’s “legislative findings” prove unfounded at the permanent injunction stage of this litigation, the State has demonstrated a reasonable relationship between the state’s interest and the GMO-labeling mandate.
  • Commerce Clause. The Plaintiffs argued that Vermont’s labeling measure violates the Constitution’s Commerce Clause because the state-based labeling measure would create an undue burden on interstate commerce, ultimately resulting in a 50-state patchwork of labeling laws. The Court was not convinced, noting that there were no other states with conflicting labeling laws. The Court dismissed the Plaintiffs’ complaint to the extent that it alleged the GMO-labeling mandate was unconstitutional under the Commerce Clause.
  • Supremacy Clause. The Plaintiffs asserted that the GMO-labeling mandate was preempted by the FFDCA, NLEA, FMIA, and PPIA. The Court was not convinced by the Plaintiffs’ arguments with regards to the FFDCA or the NLEA. However, the Court agreed that the FMIA and PPIA expressly preempted state standards for “[m]arking, labeling, packaging, or ingredient requirements in addition to, or different than, those mandated by federal law.” This means that processed and packaged foods that are subject to USDA inspection, such as canned soups or frozen dinners containing meat or poultry products, cannot be subject to state GMO-labeling mandates. Vermont has already conceded this issue in its final rule, which implements Act 120.

“Natural” Labeling Prohibition

The Plaintiffs also challenged Act 120’s prohibition on advertising and labeling of products containing genetically-engineered ingredients as “natural,” “all natural,” or words of similar import. The Plaintiffs argued that this prohibition violated the First Amendment. The Court sided with the Plaintiffs on the First Amendment argument, reasoning that prohibitions on commercial speech are subject to “intermediate scrutiny” under the Central Hudson test. The Court held that Vermont has failed to demonstrate a “substantial” state interest in prohibiting these labels. The Court also held that the “natural” labeling prohibition violated the Commerce Clause to the extent that it attempted to regulate advertising that occurred outside of Vermont.

Although the Court largely sided with the Plaintiffs on the “natural” labeling prohibition, Chief Judge Reiss did not grant a preliminary injunction on this matter, citing to a lack of proof of “irreparable harm” on the part of the Plaintiffs.

Next Steps

This first round of the litigation is certainly a setback for those in the food industry that oppose state-level GMO-labeling mandates. However, this is only the first round. The Plaintiffs have not announced their next steps. At this point, they may either (1) seek an interlocutory appeal of this decision at the Second Circuit Court of Appeals, or (2) move forward to the permanent injunction stage of this litigation.

In the meantime, support is growing for the proposed Safe and Accurate Food Labeling Act of 2015, which would preempt state GMO-labeling measures and set standards for when GMO labels could and could not be required. However, no votes have been taken on this measure and it is uncertain whether the measure has a chance of being enacted into law.

OFW Law will continue to monitor developments in this case.

Food Defense Plans

By Barbara J. Masters, D.V.M.

One of the goals of the Food Safety and Inspection Service’s Strategic Plan is to “ensure that facilities implement safeguards and systems to protect food from contamination by people who might try to intentionally and maliciously harm consumers.”  The Agency has a FY 2015 target of 90% of all establishments having a functional food defense plan. Since 2006, annual surveys have been conducted to measure progress.  The largest establishments currently exceed the goal (97% have a functional plan) while the very small establishments are not yet at the target.

The Food Safety Modernization Act (FSMA) requires the Food and Drug Administration (FDA) to implement measures to protect the food supply from intentional contamination.  A proposed rule to address hazards resulting from intentional contamination was issued on December 24, 2013.

Both FSIS and FDA have taken substantial measures to assist the food industry in the development of food defense plans.  The FSIS webpage includes a tool that an establishment can download to select the specific elements appropriate for their facility.  FDA maintains an on-line food defense plan builder free to all users.  Once a plan is documented, the establishment must implement the plan.  Steps to implementing a food defense plan include:

  • Testing the plan (e.g., check locked doors, take unannounced walks around the perimeter), and
  • Reviewing and maintaining the plan (review and update as needed).

Food defense plans should be tailored to the facility.  Small establishments do not need to make the plan overly burdensome.  For example, a plant that only employs family members would not need background checks on employees as a critical element.  However, this establishment could document the use of door locks and outdoor lighting at key locations in the facility.

Areas to be considered in a food defense plan are: outside security, inside security, personnel security measures and incident response security measures.

When I go visit any establishment, I am always asked to show my identification.  I am always escorted during the visit, and I see emergency plans posted at every facility.  These are all elements of a food defense program.  If these elements for secure food are already in place, it is logical that they could easily be documented and verified by the establishment.

I encourage those plants that are not currently maintaining a functional food defense plan to review the FSIS and FDA websites.  I challenge them to consider that they very likely already have all the elements in place for a food defense plan – the plan just needs to be documented.  By documenting the plan – the establishment is taking the necessary steps to ensure all team members are aware of the program and are taking steps to consistently implement it.

If by maintaining a functional food defense plan we can contribute to a safer and more secure food supply, then I am certain we are all in favor of meeting this objective.

FDA Provides Another Guidance Concerning FDA’s Use of Foreign Study Data

By Mason Weeda

FDA’s Center for Devices and Radiological Health (“CDRH”) and Center Biologics Evaluation and Research (“CBER”) recently published a new draft guidance entitled “Acceptance of Medical Device Clinical Data from Studies Conducted Outside the United States [(“OUS”)] (“Draft Guidance”) (available here). With this Draft Guidance, FDA aims to minimize the possibility for additional or duplicative U.S. studies, to harmonize global clinical trial standards, and to promote public health and innovation.

The Draft Guidance adds to a myriad of policies, statutory and regulatory provisions, and proposed rules on OUS studies, including:

  • FDCA § 569B (or 21 U.S.C. § 360bbb-8) which requires FDA to accept data from clinical investigations conducted OUS, in deciding whether to approve or clear a device. Pursuant to §569B, if FDA finds that such data are inadequate under applicable standards to support clearance or approval of the device, then FDA must provide the sponsor with written notice of the finding and FDA’s rationale.
  • 21 C.F.R. § 814.15 which provides that OUS clinical study data submitted in support of a Premarket Approval Application (“PMA”) and conducted under an Investigational Device Exemption (“IDE”) shall comply with Part 812. If an OUS study in support of a PMA is not conducted under an IDE, FDA will accept studies which have been conducted outside the United States and begun after November 18, 1986, “if the data are valid and the investigator has conducted the studies in conformance with the ‘Declaration of Helsinki’ or the laws and regulations of the country in which the research is conducted, whichever accords greater protection to the human subjects.” If relying on a study that started before November 19, 1986, FDA must be satisfied that “the data are scientifically valid and that the rights, safety, and welfare of human subjects have not been violated.” A PMA based solely on foreign clinical data and otherwise meeting the criteria for approval under this part may be approved if the foreign data are: “applicable to the U.S. population and U.S. medical practice;” “have been performed by clinical investigators of recognized competence;” and “considered valid without the need for an on-site inspection by FDA or… FDA can validate the data through an on-site inspection or other appropriate means.”
  • Proposed Rulemaking. Over two years ago, FDA published a proposed rule on “Human Subject Protection; Acceptance of Data from Clinical Studies for Medical Devices.” The proposed rule, when finalized, would require that foreign clinical studies in support of PMAs, IDEs, HDEs and 510(k)s be conducted in accordance with good clinical practice (“GCP”).
  • 2001 Guidance. In March 2001, FDA issued guidance on acceptance of foreign clinical studies titled “Guidance for Industry-Acceptance of Foreign Clinical Studies”, which describes the acceptance of foreign clinical studies in support of an application for marketing approval of human drugs, medical devices and biological products. This guidance merely clarifies that FDA incorporated the 1989 Declaration of Helsinki in its regulation governing investigational drug trials conducted in foreign countries and that it was not amending the regulation to incorporate the 2000 amendments to the Declaration.

The Draft Guidance elaborates on FDA’s regulation and provides some insight on what FDA may focus on when evaluating the adequacy of an OUS study. Not surprisingly, FDA makes it clear that sponsors should seek input from FDA prior to initiating an OUS device study to ensure that it will generate adequate and valid scientific data. The Draft Guidance essentially provides three primary considerations related to relying on OUS clinical data:

  • Differences in study populations. To the extent a device has disparate safety effects in different demographic groups, differences in the race, ethnicity, age, gender and sex of a foreign population can affect the applicability of the study to the intended U.S. population. Reporting on the representation of such groups in the device submission allows appropriate sub-group analyses. The foreign population and the intended U.S. patient populations may also differ in the prevalence of clinical factors that can affect risks of an intervention as well as clinical response.
  • Differences in clinical conditions. Differences in OUS clinical conditions versus those in the U.S. can affect the relevance of the data to the intended U.S. population. OUS countries may have different standards of care, clinical facilities, or levels of clinical skill which can cause OUS data to not be generalized to U.S. clinical practice and which can impact the data’s usefulness in supporting the safety and/or effectiveness of the device.
  • Differences in regulatory requirements. When studies conducted OUS are initiated to satisfy the requirements of foreign countries, the studies may not be designed to address the questions necessary to satisfy FDA requirements.

The Draft Guidance provides a number of useful examples that demonstrate the application of the above considerations. Although the proposed rulemaking on “Acceptance of Data from Clinical Studies for Medical Devices” is not yet final, the Draft Guidance concludes by highlighting the importance of GCP. It states that “showing compliance with GCP is one way sponsors of device applications may be able to show that their OUS data comply with applicable FDA requirements.” FDA’s requirements for IDE studies address GCPs through applicable regulations, such as 21 C.F.R. Part 50, 54, 56 and 812. The Draft Guidance also provides that FDA considers the following two standards to be GCP principles that articulate ethical and policy standards for OUS clinical trials:

  • ICH E6, “Good Clinical Practice: Consolidated Guidance,” and
  • ISO 14155 “Clinical Investigation Of Medical Devices For Human Subjects – [GCP]”

FDA is requesting comments on the Draft Guidance before it begins work on the final guidance. The Agency will be accepting comments until July 21, 2015.

Warning Letters Update

By Mason Weeda

This past week FDA made a number of Warning Letters available on its website, with issues ranging from Juice HACCP to cGMPs for finished pharmaceuticals. A Warning Letter is informal and advisory, with the aim to achieve voluntary compliance and to establish prior notice. It communicates the agency’s position on a matter, but it does not commit FDA to taking enforcement action. Basically, you should read Warning Letters relevant to your industry because they can provide you with examples of what not to do. Here’s a quick run-down of Warning Letters published this week that we thought merited a closer look:

  • FDA issued a March 31, 2015 Warning Letter to Hospira S.p.A. for alleged violations of current good manufacturing practice regulations (cGMP) for finished pharmaceuticals at a manufacturing plant in Italy. The Warning Letter provides that Hospira failed to:
    • establish procedures to prevent microbiological contamination of sterile drug products and include validation of sterilization processes;
    • thoroughly investigate any unexplained discrepancy or failure of any batch;
    • exercise appropriate controls over computer or related systems so that only authorized personnel institute changes in master production/controls records; and
    • ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards.

The Warning Letter details Hospira’s failure to evaluate certain airflow studies, and its improper rejection of various vials during the manufacturing process without explanation. Ultimately, FDA stated that Hospira’s response to its inspectional observations lacked adequate corrective action.

  • FDA issued March 27, 2015 Warning Letters respectively to Avanti Health Care and Kings Pharmacy regarding deficiencies in their practices for producing sterile drug products. Both firms compound drugs and registered with FDA as outsourcing facilities and, therefore, were required to, among other things, comply with the Compounding Quality Act and cGMP requirements. Though Avanti was cited for six (6) cGMP violations and Kings was cited for three (3), the letters are very similar in many respects. During the inspections of both facilities, respectively, FDA observed that, among many violations, drug products were prepared under insanitary conditions, where operators failed to use proper aseptic technique in designated areas. Both firms also failed to include mandatory labeling for compounded products (i.e., “this is a compounded drug” and “not for resale”). These letters demonstrate FDA’s ongoing effort to more closely regulate and inspect outsourcing facilities. Avanti registered as an outsourcing facility on April 21, 2014, and FDA began its inspection only two (2) months later on June 23; Kings Pharmacy registered on December 23, 2013, and was inspected just three (3) months later.
  • FDA issued a March 25, 2015 Warning Letter to Skin Authority, LLC for making promotional claims on its website that indicate that its products, though labeled as cosmetics, were, in fact, promoted as drugs. The Warning Letter lists examples of drug claims for serums, scrubs and creams made on the website, including, for example, “help inhibit cellular breakdown,” “foster skin growth,” “help counteract infection,” “improve anti-inflammatory response,” and “increase cell growth.” The products were not generally recognized as safe and effective for the uses listed on the website, were not subject to any FDA-approved New Drug Application, and, therefore, were “new drugs” that required FDA approval prior to marketing.

The information that the agency communicates in a Warning Letter can be invaluable as it provides important, cautionary lessons for regulated industry and provides a view into the agency’s current thinking. You can keep tabs on Warning Letters by checking our blog periodically or by looking on FDA’s Warning Letters webpage.

Food Facility Registration Rules To Be Updated by FDA

by Michael J. O’Flaherty

FDA has published a proposed rule that would amend and update its regulatory requirements governing registration of food facilities.

The Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (the Bioterrorism Act), which essentially directed FDA to take steps to protect the public from a threatened or actual terrorist attack on the U.S. food supply, added section 415 to the Federal Food, Drug, and Cosmetic Act (FD&C Act). Among other actions taken to implement the Bioterrorism Act, pursuant to section 415 the agency established regulations requiring that food facilities register with FDA. These regulations became effective on December 12, 2003.

The FDA Food Safety Modernization Act (FSMA) of 2011 amended section 415 of the FD&C Act to require that facilities engaged in manufacturing, processing, packing, or holding food for consumption in the U.S. submit additional registration information to FDA, including an assurance that FDA will be permitted to inspect the facility at the times and in the manner permitted by the FD&C Act. As amended, section 415 also requires food facilities to renew their registrations every other year, and provides FDA with authority to suspend the registration of a food facility in certain circumstances. FDA has issued a number of guidance documents to assist the industry in complying with the food facility registration requirements. See generally Guidance for FDA Staff: Compliance Policy Guide Sec. 100.250 Food Facility Registration – Human and Animal Food (June 2014); Guidance for Industry: Questions and Answers Regarding Food Facility Registration (Sixth Edition) (rev. Nov. 18, 2014); Guidance for Industry: What You Need to Know About Registration of Food Facilities; Small Entity Compliance Guide (rev. Dec. 17, 2014); and Guidance for Industry: Necessity of the Use of Food Product Categories in Food Facility Registrations and Updates to Food Product Categories (rev. May 18, 2014)..

Under FDA’s present regulations, certain food facilities, including retail food establishments, are exempted from the requirement to register. The proposed rule would amend the regulatory definition of a “retail food establishment” in a way that would expand the number of establishments that are subject to the exemption. A retail food establishment is currently defined as an establishment that sells food products directly to consumers as its primary function. An establishment’s primary function is to sell food directly to consumers if the annual monetary value of sales of food products directly to consumers exceeds the annual monetary value of sales of food products to all other buyers. The proposed rule would clarify that, in determining the primary function of an establishment, the sale of food directly to consumers from an on-farm establishment includes sales by the establishment at such direct sales platforms as roadside stands, farmers’ markets, and Community Supported Agriculture (CSA) programs. Based on currently available data, FDA estimates that there are approximately 71,000 farms that only sell food products directly to consumers in ways that include farmers markets, roadside stands, and CSA programs. [Note: Inasmuch as the amended definition would exempt additional establishments from the requirement to register, these establishments also would not be subject to the requirements of the FSMA preventive controls rulemakings, which apply to facilities that are required to register.] See generally Questions and Answers for Farmers on FSMA Proposed Rule for Food Facility Registration (rev. Apr. 8, 2015).

For food facilities that are not exempt from registration, the proposed rule would add new provisions to the current regulations to codify certain requirements of FSMA that were self-implementing and effective upon enactment of FSMA. Those requirements are:

  • Registrations for domestic facilities must contain the email address of the contact person of the facility, and registrations for foreign facilities must contain the email address of the U.S. agent for the facility.
  • Food facilities that are required to register with FDA must renew their registrations every two years, between October 1 and December 31 of each even-numbered year.
  • All food facility registrations must contain an assurance that FDA will be permitted to inspect the facility at the times and in the manner permitted by the FD&C Act.

In addition, the proposed rule would add certain new requirements, including:

  • All food facility registrations would be required to be submitted to FDA electronically; however, this requirement would not take effect before January 4, 2016.
  • Registrations would be required to contain the type of activity conducted at the facility for each food product category.
  • The proposed rule would provide for measures to verify certain information submitted in registrations.
  • The proposed rule would identify additional circumstances under which FDA will cancel registrations (i.e., FDA independently verifies that the facility is not required to register; information about the facility’s address was not updated in a timely manner; the registration was submitted by a person not authorized to submit it).

Public comments on FDA’s proposed rule may be submitted electronically or by regular mail until June 8, 2015.

FDA DRAFT Guidance: “Ensuring Safety of Animal Feed Maintained and Fed On-Farm”

By Jolyda O. Swaim

In earlier blogs, I have mentioned having horses and other animals while growing up on a small farm.  Even now, to my husband’s dismay, I have never outgrown being “horse crazy.”  But during all this time, I never remember being concerned about the animal feed I have purchased or used.  I do qualify this statement in that I knew certain things could not be fed to horses and that you better know where your sawdust was coming from to ensure it did not include black walnut.  But as to the commercial feed I purchased – I never gave it a thought.

Recently, the FDA issued a draft guidance entitled “Ensuring Safety of Animal Feed Maintained and Fed On-Farm.”  Comments on the draft are due by June 3, 2015.

This guidance is intended to help animal producers – those who feed animals, including horses – in developing and implementing on-farm practices to ensure animal feed is maintained and fed in a safe manner.  It provides good information for not only those feeding animals commercially, but for those who have one or two animals in the backyard they are raising for personal use.

In general, the guidance encourages people feeding animals to consider and apply the following principals:

  1. Know what feed contaminants may be present in your animals’ feed and the measures known to prevent such contaminants from becoming unacceptable feed risks;
  2. Obtain feed from safe and reliable sources;
  3. Recognize unexpected changes in the feed at your farm (e.g., changes in color, smell, texture, or appearance);
  4. Know where in your production system unacceptable feed risks may occur;
  5. Monitor animal feed products for contaminants during receiving, holding, and handling; and
  6. Be aware that other actions, such as limiting access to the premises to authorized personnel, following feed labeling directions, proper personnel training, and sampling and testing of feed, can help ensure feed safety.

The definition of “feed contaminants” are “any biological, chemical, physical, or radiological agent that if present in feed has the potential to cause illness or injury to animals or humans.”  Appendix A to the draft guidance lists examples to be considered.  When a contaminant rises to the level that is “reasonably likely to cause illness or injury in animals or humans,” this is considered an “unacceptable feed risk.”  Appendix A also lists examples of these.

The guidance provides a number of sources for review that identify feed contaminants that can be associated with particular types of farms and feed activities.  These include:

The guidance also has recommendations for safe feeding practices that farms should consider adopting such as knowing the requirements for animal feed in your state, and  taking steps to prevent or significantly minimize the occurrence of feed contaminants in feed (e.g., pest control measures, regular and adequate cleaning of animal feeding areas and equipment, good storage practices) among others.  Information is even provided regarding your pastures and bedding – think my comment on sawdust!

Many considerations relate to how you store feed, such as the need to ensure use of oldest first, and that the correct feed is used for each animal.  The guidance also has recommendations for farms with intensive animal feeding operations.  Other information includes safe use of pesticides, fertilizers, and other agricultural chemicals, personnel training and sampling and analyzing feed.

Finally, FDA provides information on steps to take if you have a concern about feed safety.  These include:

  1. Take immediate measures to ensure the product is not fed to animals;
  2. Review the FDA website about reporting problems to the agency;
  3. Promptly consult a veterinarian if feed may cause or has caused a negative effect on animal health; and
  4. If you suspect there could be a negative effect on human health from ingestion of food products derived from animals that ate contaminated feed, promptly contact local and state health departments.

The guidance provides thoughtful advice on what should be considered when feeding animals on small or large farms and should be reviewed by anyone with a few animals to many animals.

Tip

At minimum, after you dump that bag of feed into your grain bin, cut off the label with the lot number and maintain it in a plastic bag!  Always keep the current feed’s label(s) in the plastic bag.  This way, if something does go wrong, you have the information on what you last fed your animal/s.  This goes for whatever type of animal you are feeding, including your dogs and cats.  With this information, you won’t be trying to figure out whether or not what you have in that storage container is part of the most recently-announced recall!