PRN Publishing, a company that distributes a monthly newsletter for community pharmacists, filed this citizen petition in 2008 over concerns about pharmacists’ ability to determine the equivalency status of prescription drug products. (See the full text of PRN’s citizen petition here.) When filling prescriptions, pharmacists often refer to the list of Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the Orange Book, to determine the equivalence status of brand and generic drug products in the United States. Where substitution is not prohibited by a prescriber, pharmacists have a duty to dispense only those generic products which appear in the Orange Book and are rated “A.” The citizen petition argued that, due to frequent changes in drug manufacturers and distributors of particular drugs, pharmacists may have difficulty matching drug products on the shelves with the corresponding listing in the Orange Book. As a solution, PRN suggested that all prescription drug manufacturers and distributors should include a drug product’s NDA number on the label of each bottle. Thus, this system would allow pharmacists “to quickly and easily determine the equivalence status of any drug product by simply comparing the NDA number on the bottle to the NDA numbers listed in the Orange Book under the heading of the particular drug in question.”

Currently, 21 C.F.R. part 314 requires that all drug manufacturers obtain FDA approval of a drug application in order to market a new drug or generic drug. Manufacturers and distributors, however, are not required to place this approved application number on drug product labels. Section 10.30 of the Code of Federal Regulations provides citizens the opportunity to submit a petition to the FDA requesting the Agency to add, remove, or change its regulations. (See 21 C.F.R. § 10.30.) In its citizen petition, PRN suggested that the change to Agency requirements would benefit all stakeholders because it would 1) protect patients from inadvertent illegal substitution; 2) relieve pharmacists of the undue burden of having to research the provenance of each drug product before dispensing generics; and 3) guarantee drug makers that a company’s NDA is “firmly attached to its product in whatever form it is distributed.”

Upon reviewing this citizen petition, the FDA did not find PRN’s recommendation to be an effective means of communicating drug equivalence to pharmacists. (See the full text of FDA denial here.) In its denial, the FDA pointed out that authorized generic drugs share the same NDA numbers as the branded innovator product and would not be identified separately from the branded drug in the Orange Book. The FDA addressed this issue in the introductory section of the 28th edition of the Orange Book. There, the FDA specifically indicated that distributors and repackagers of products in the Orange book are not identified “because [they] are not required to notify FDA when they shift their sources of supply from one approved manufacturer to another.” Consequently, “it is not possible to maintain complete information linking product approval with the distributor or repackager handling the product.”

Further, the FDA asserts that PRN’s recommendation may result in confusion because “[p]harmacists could be confused when they look up an NDA number in the Orange Book and find only a listing for the innovator product.” The FDA noted that the citizen petition lacked sufficient data or information to support the claims listed. After balancing PRN’s claims against the Agency’s statutory mandate, space limitations, alternatives, potential for confusion, and potential safety risk, the FDA concluded that it would not be necessary to amend the current drug labeling requirements at this time and denied PRN’s citizen petition.

Fuerst Ittleman will continue to monitor the developments in the regulation of drug products. For more information, please contact us at contact@fuerstlaw.com. 

The FDA, through the Center for Biologics Evaluation and Research (CBER) and Office of Regulatory Affairs (ORA), is responsible for the regulation of the collection of blood and blood components used for transfusion or for the manufacture of pharmaceuticals derived from blood and blood components.  Pursuant to Section 351 of the Public Health Service Act (“PHS Act”) and the Food, Drug, and Cosmetic Act (“FDCA”), the FDA oversees and enforces quality standards, conducts inspections of blood establishments, and monitors reports of errors, accidents and adverse clinical events.

The FDA inspects blood establishments to ensure that products are manufactured safely and in a way that protects the purity, potency and quality of the blood products. In addition, the FDA requires blood establishments to properly screen donors, maintain good manufacturing practices (cGMPs), maintain accurate records, investigate any breaches of establishment safeguards, and correct system deficiencies. Licensed blood facilities may engage in the sale, transport, and exchange of blood and blood products across state lines.

Failure to comport with the FDA’s regulations may result in enforcement action in the form of a fine, as in the Red Cross’s case, regulatory action letters, or revocation of establishment licensure.  In previous years, the FDA has entered into Consent Decrees with several blood bank establishments, such as the American Red Cross and the New York Blood Center, for violations of cGMPs and inadequate quality assurance programs. The FDA has also suspended the license of a blood center (Intermountain Health Care) due to numerous cGMP violations. Although the FDA has expressed its continued commitment to upholding high standards for blood collection and blood bank establishments, the onus of compliance with the FDA’s regulations and the safety of the nation’s blood supply rest in the hands of the individual blood establishments.

Fuerst Ittleman will continue to monitor the FDA’s regulation of biologics products and establishments. For more information, please contact us at contact@fuerstlaw.com

The FDA classifies medical devices based on perceived risk using a 3-tier system. Class I medical devices have the lowest perceived risk, and generally do not require a formal FDA review before marketing. Class II medical devices have a higher perceived risk than Class I, and require the submission of a 510(k) or premarket notification application (PMA) to establish the safety and effectiveness of the device. Class III medical devices have the highest perceived risk, and require the submission of a PMA. The Agency believes the safety and effectiveness of the newly exempt devices is sufficiently well established and a 510(k) review is not necessary.

The guidance states that the FDA intends to propose an amendment to the classification regulations to exempt the specified Class I devices from the 510(k) requirements that apply pursuant to section 510(I) of the Federal Food, Drug, and Cosmetic Act. In addition, the FDA intends to propose the downclassification and exemption from the 510(k) requirements for the specified Class II devices. The FDA states that the in vitro and radiology Class II devices now receiving a 510(k) exemption are sufficiently well-established and have sufficiently controlled the risks that are necessary to assure the safety and effectiveness; thus, those devices can now be reclassified as Class I. In the interim period while the FDA finalizes such exemption and downclassification, the FDA intends to exercise enforcement discretion with regard to 510(k) submission requirements for the devices listed in the guidance.

The FDA’s review of medical devices through the 510(k) process is complex. Fuerst Ittleman has extensive experience successfully navigating medical devices through FDA review. For more information on FDA’s review of medical devices, please contact us at contact@fuerstlaw.com.

The draft guidance clarifies the difference between unsolicited and solicited requests, and also differentiates between requests that are public and non-public. Solicited requests are requests for information that are “prompted in any way by a manufacturer or its representatives.” According to the draft guidance, the FDA may consider a solicited request as evidence of a firm’s intent to support or market a drug or medical device for a condition or use that has not been approved by the FDA.

Unsolicited requests, on the other hand, are “initiated by persons or entities that are completely independent of the relevant firm.” A public unsolicited request is made in a public forum. A question about off-label use of a specific product during a live presentation is one example of a public unsolicited request. A non-public unsolicited request is directed privately to a firm using a one-on-one communication approach. An example of a non-public unsolicited request is a call or e-mail for off-label use to medical information staff at a firm.

The FDA remains committed to its long-standing position that “firms can respond to unsolicited requests for information about FDA-regulated medical products by providing truthful, balanced, non-misleading, and non-promotional scientific or medical information that is responsive to the specific request, even if responding to the request requires a firm to provide information on unapproved or uncleared indications or conditions of use.” For any response made to a non-public unsolicited request for off-label information, the FDA recommends that a firm provide information only to the individual making the request. In addition, the information contained in the response should conform to the following:

- Information should be tailored to answer only the specific question(s) asked;

- Information should be truthful, non-misleading, accurate, and balanced;

- Information should be scientific in nature; and

- Information should be generated by medical or scientific personnel, independent from sales or marketing departments. 

In addition, the distributed information should be accompanied with a copy of the FDA-required labeling, a statement disclosing the indications for which the FDA approved or cleared the product, and a statement notifying the recipient that the FDA has not approved or cleared the product as safe and effective for use. If a firm’s response conforms to the FDA’s new draft guidance, the FDA would not use the response as evidence of the firm’s intent to unlawfully support or market the product for an unapproved or uncleared use.

The FDA also addressed responses to public unsolicited requests for off-label information made through electronic media. Although the FDA recognizes that addressing off-label use to the general public can result in potential benefits to the public health, the agency continues to have significant concerns about broad, public responses. First, the FDA is concerned that product information posted on websites or other public forums may provide information about off-label use to individuals who have not requested such information, and would thus promote a product for a use or condition not approved or cleared by the FDA. Secondly, the FDA is concerned that the information posted on websites or other public forums would be available for an indefinite amount of time, and could pose a serious risk to public safety if new scientific advances render the posted information outdated or obsolete. Based on these concerns, the FDA recommends that firms only respond to requests pertaining specifically to its own named product. Further, firms should omit any information pertaining to off-label usage, should provide the individual requesting information with the firm’s contact information, and should recommend that the individual contact a medical/scientific representative with the specific unsolicited request to obtain more information. Any public response should disclose a representative’s relationship to the firm and should not be promotional in nature. 

In addition to this draft guidance, the FDA also issued a notice in the Federal Register on December 28, 2011, announcing the comment-period for scientific exchange. (For the full text of this notice, please click here.) At present, FDA regulations do not restrict the promotion of the “exchange of scientific information” regarding an investigational drug or device. The FDA, however, has yet to define the scope of scientific exchange. This notice, a direct response to a Citizen Petition jointly filed by several major pharmaceutical manufacturers, seeks comments on all aspects of scientific exchange communications and activities related to off-label uses of marketed drugs, biologics, and devices and use of products that are not yet legally marketed.

Specifically, the FDA seeks comments on how “scientific exchange” should be defined, what types of activities fall under scientific exchange, how to determine the players involved in scientific exchange, how it should be distinguished from promotion, and how the FDA should treat scientific exchange for products that have not been approved or cleared by the FDA. These comments will help the FDA to evaluate its policies on off-label uses and possible pre-approval communications. The FDA will accept comments through March 27, 2012.

Fuerst Ittleman will continue to monitor any developments in the FDA’s regulation of off-label uses for medical drugs and devices. For more information, please contact us at contact@fuerstlaw.com.

First, because these products are intended for use in the diagnosis, cure, mitigation or treatment of disease, they are considered drugs by the FDA. Noting that HCG is a FDA-approved prescription drug, FDA has found that these products are “new drugs” within the meaning of the Federal Food, Drug & Cosmetic Act (FDCA). Under the FDCA, a “new drug” is defined as:

[a]ny drug . . . the composition of which is such that such drug is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the condition prescribed, recommended, or suggested in the labeling thereof.

21 U.S.C. § 321(p).

In targeting these HCG diet products, the FDA has determined that they constitute “new drugs” under the FDCA because companies marketing the products do not possess any evidence showing that the drugs are recognized as safe for their intended uses.

Further, with cooperation from the Federal Trade Commission (FTC), the agencies have targeted these companies for making unsubstantiated claims regarding the effectiveness of HCG products. While both agencies require that promotional statements be truthful and non-misleading, the recent Warning Letters allege that these companies do not possess the necessary scientific evidence to support their weight loss claims.

Under the FTC Act, the FTC has shared jurisdiction with the FDA over claims made in the marketing of FDA-regulated products. Thus, when FDA-regulated products, like the HCG diet products in the present circumstances are at issue, the agencies often work together to target non-compliant parties, with both being able to require companies to take corrective action. For more information about FDA and FTC cooperative efforts, see our previous report here.

For more information regarding FDA and FTC enforcement measures or compliance, please contact us at contact@fuerstlaw.com

An IDE allows investigational devices to be used in feasibility or clinical studies in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification [510(k)] submission to the FDA. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE
before the study is initiated. 21 CFR 812. Please see our previous report for more information concerning PMA and 510(k) submissions for medical devices.

Draft Guidance for Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies

The draft guidance regarding IDE applications for early feasibility studies applies to medical devices of significant risk in the early stages of development. Early feasibility studies allow for early clinical evaluation of devices to provide proof of principle and initial clinical safety data to better inform the final design of the device. The guidance permits studies to start earlier in the device development process than previously allowed. However, initiation of early feasibility studies must be justified by a risk-benefit analysis and adequate human subject protection measures. The new draft guidance also permits select device modifications to be made without FDA approval.

FDA Decisions for Investigational Device Exemption (IDE) Clinical Investigations

The draft guidance regarding IDE applications for clinical investigations clarifies the FDA’s process for approving clinical trials of medical devices. The draft guidance describes the Agency’s methods which allow clinical investigations of devices to begin under certain circumstances even when there are outstanding issues regarding the IDE application. Those methods include: approval with conditions, staged approval, and communication of outstanding issues related to the IDE through future considerations.

The FDA permits an IDE application that receives an approval with conditions to enroll patients in studies while certain issues are being resolved. Those issues may include: data analysis methods that can be resolved prior to gathering the data, minor divergences from study endpoints, or study design assumptions. A staged approval allows studies to begin with a smaller group of subjects while applicants gather additional data, prior to beginning larger general enrollment.

Fuerst Ittleman is well-equipped to assist members of FDA-regulated industry navigate the laws and regulations applicable to medical devices. For more information about the current regulatory framework surrounding medical devices, please contact us at contact@fuerstlaw.com.

In the Merck case, because the company was actively involved in marketing Vioxx for uses that were not approved by the FDA, it was charged with introducing a misbranded drug into interstate commerce. Under 21 U.S.C. § 352(f)(1) a drug is deemed misbranded if it fails to bear adequate directions for use. Under the FDCA and its accompanying regulations, the FDA approves drugs for specific uses by requiring sponsors to submit data showing drugs are safe and effective for their intended uses and limits the promotion of drugs to these specified uses by approving proposed labeling. Because Vioxx was promoted for a use not shown in the product labeling, it was considered misbranded by the FDA as the label failed to display this indication and thus lacked adequate directions for use.

For more information about the FDA drug approval process, please contact us at contact@fuerstlaw.com.

While this suit was recently instituted against ATF, the Complaint shows how the company has been on FDA’s radar since 2004. According to FDA, ATF has “a long history of violating the Act.” In March 2004, FDA issued a Warning Letter to the Company in connection with its distribution of an adulterated dietary supplement. Later, in November 2004, FDA issued another Warning Letter, citing the president of ATF for the distribution of adulterated dietary supplements. Finding that ATF was not taking proper corrective actions to remedy these violations, the warnings ultimately culminated in a seizure action in 2006, detailed here. The most recent FDA action began after a FDA inspection conducted in March-April 2011 revealed several deviations from FDA’s current good manufacturing practices (cGMPs). In particular, FDA found that several ingredients and products were being substituted during the manufacturing process without the changes being reflected in product labeling.

In addition to cGMP violations, FDA’s inspection also revealed that ATF failed to report serious adverse events. Under 21 U.S.C. § 379aa-1, manufacturers of dietary supplements are required to notify the FDA within 15 days of learning of a serious adverse event. A serious adverse event is defined under the Act as an event that results in:

(i) death; (ii) a life-threatening experience; (iii) inpatient hospitalization; (iv) a persistent or significant disability or incapacity; or (v) a congenital anomaly or birth defect.

21 U.S.C. § 379aa-1(a)(2).

According to the FDA, ATF received a complaint that one of its customers had experienced a spike in blood pressure and mild heart attack, requiring hospitalization. Despite having received this complaint in July 2010, ATF did not report this event, resulting in what FDA claims was another violation of federal law.

Given the past violations of the FDCA and the several deficiencies discovered upon the recent inspection, FDA ultimately instituted the present action against ATF. While warning letters are not uncommon, the remedial measures that companies take in response to them are often determinative of how the FDA will proceed.

For more information about FDA enforcement action or regulatory compliance, please contact us at contact@fuerstlaw.com.

FDA’s Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals are set forth in 21 C.F.R. part 211. These regulations provide the minimum standards for which manufacturers must follow and cover a range of manufacturing activities, including required personnel, standards for sanitation of buildings and equipment, as well as recordkeeping requirements and laboratory controls. In the present case, Mylan was cited for various CGMP violations, including failure to establish required laboratory controls. In particular, FDA cited the company for failing to test each patch of its drug product to ensure that it conforms to final specifications for the drug product, as provided by 21 C.F.R. § 211.165(a).

While the violations cited in the Warning Letter were observed upon FDA inspections of Mylan’s plant earlier this year, the Letter was issued only recently after the company failed to demonstrate to the FDA that it has taken all necessary corrective actions. In addition to notifying the particular firm, FDA Warning Letters notify the public that a particular firm has allegedly violated federal law. Thus, given the bad publicity that these letters generate, it is advantageous for firms to correct possible violations even before the FDA issues Warning Letters.

For more information about CGMP requirements or FDA enforcement action please contact us at contact@fuerstlaw.com.

Found here, Hills’ Complaint alleges that the FDA’s approvals of Identi’s ANDAs were arbitrary and capricious. In short, Hill alleges that in approving the ANDAs, FDA treated Identi differently and in contravention of the FDCA by foregoing certain testing to show that the drugs are safe for consumers. Because Derma-Smoothe is a topical treatment derived from peanut oil (a major allergen), FDA required Hill to perform testing to show that the refined oils in the drug contained only trace amounts of amino acids. Still required to test every batch it produces, Hill claims that it has “invested more than $1 million to license and develop a proprietary amino-acid analysis.” Because the methods Hill uses to test its products are proprietary, Hill alleges based on information and belief that FDA has approved Identi’s applications without requiring such testing or verification that Identi’s drugs have similarly low levels of amino acid.

Further, because Hill is required to declare that Derma-Smoothe has undergone such testing on the label of each product, Hill claims that Identi’s products cannot be approved as a generic form of Derma-Smoothe because the drug cannot contain such a declaration in product labeling. Under FDA regulations, generic formulations of drugs undergo approval through an Abbreviated New Drug Application (ANDA). Unlike a New Drug Application (NDA), an ANDA requires the manufacturer to demonstrate that its drug is bioequivalent to a drug approved via an NDA. This showing generally requires the generic to demonstrate that it contains the same active ingredients, is used in the same manner and will bear largely the same labeling. Thus, assuming the Hill case survives a motion to dismiss filed by the FDA, the Hill case will confront the extent of the differences that are permissible in product labeling in order for the Agency to make a finding of bioequivalence under the FDCA.  

Fuerst Ittleman will continue to monitor the developments of the Hill case. For more information regarding the ANDA generic drug approval process or for any questions regarding how your company can maintain FDA regulatory compliance, please contact us at contact@fuerstlaw.com.