On June 25, 2018, the Food and Drug Administration (“FDA”) approved Epidiolex (cannabidiol), the first marijuana derived drug for use in the United States, to treat two rare forms of epilepsy. This decision for the FDA could have sweeping effects for the marijuana industry. While the FDA has previously approved drugs comprising synthetic (manufactured) cannabinoids, this is the first FDA approved drug comprised of an active ingredient derived from marijuana. Even with FDA approval, further action is required before Epidiolex can enter the market in the United States.

Epidiolex will be the first pharmaceutical form of the cannabinoid cannabidiol, or “CBD.” CBD is a chemical component of the Cannabis sativa plant commonly known as marijuana. Unlike tetrahydrocannabinol or “THC” (a different and highly discussed cannabinoid found in marijuana), CBD is not known to have psychoactive affects. However, because CBD derived from marijuana is considered part of the marijuana plant, it is currently listed as a Schedule I controlled substance and illegal for all uses in the United States.

The Drug Enforcement Administration (“DEA”) must reclassify CBD in order for Epidiolex to be cleared to enter the market in the United States. This process will likely take months and is currently the topic of much speculation. There are five schedules for controlled substances and each controlled substance is scheduled based on whether there is a current acceptable medical use in the United States, their relative abuse potential, and the likelihood of causing dependence when abused. Schedule I drugs have no accepted medical use. Thus, CBD’s classification as such is clearly contrary to the FDA’s recent decision. It is unclear how the DEA will reschedule CBD or if it will expand reclassification to include the entire marijuana plant (this latter option is highly unlikely).

Once Epidiolex enters the market, it may be prescribed beyond the few FDA approved uses. Epidiolex has been approved for the treatment of two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome. Doctors, however, generally have the ability to prescribe drugs for unapproved, or “off-label” use. The FDA has generally accepted such procedures for various reasons.

While Epidiolex’s approval is significant, FDA Commissioner Scott Gottlieb made clear in a press release that it is not an approval of marijuana or all of its components. That said, the federal government, through the FDA, has now officially recognized that there are some medical benefits to the marijuana plant, suggesting that there is a path forward leading to the legalization of marijuana at the federal level for healthy, medical-based use of marijuana. Of course, such use has been backed by thorough research, which is essential to any future approvals of similar or new marijuana derived products. In sum, as a result of the FDA’s decision, we are likely to see the DEA reclassify CBD, which may pave the way for more developments and subsequent approval of products with CBD.

On May 3, 2018, the U.S. Department of Agriculture (“USDA”) released its much-anticipated proposed rule to establish a national standard for the disclosure of bioengineered ingredients in certain food products. The public comment period on the proposal has begun and runs through July 3, 2018. The proposed rule sheds light on certain aspects of the disclosures that food manufacturers and others will be required eventually to provide. But the USDA’s proposal leaves significant questions unanswered, providing an opportunity for the public to shape the final rule in critical ways.

Background

The USDA’s rule is promulgated under the 2016 National Bioengineered Food Disclosure Standard Act. It preempts the GMO labeling regimes of several states, including Vermont, and requires the USDA to issue a final rule on the disclosure of bioengineered ingredients in food products by July 29, 2018. You can read more about the background of the Act and the actions undertaken by the USDA prior to the release of its proposed rule here.

Definition of “Bioengineered” Ingredients

The proposed rule requires disclosure of “bioengineered” ingredients. Under the Act, “bioengineered” (or “BE”) means food “(A) that contains genetic material that has been modified through in vitro recombinant deoxyribonucleic acid (DNA) techniques; and (B) for which the modification could not otherwise be obtained through conventional breeding or found in nature.”

The proposed rule is silent as to whether ingredients that are genetically modified through other techniques, such as gene editing, are covered. But the USDA does provide some clarifying guidance on what constitutes a “bioengineered” food or ingredient. Its proposed rule offers a list of “Commercially Available BE Foods” that have been “highly adopted” in the food industry, and a list of “Commercially Available BE Foods” that are “not highly adopted.” Only food products containing ingredients on these lists will be subject to the anticipated disclosure rules.

Foods are “highly adopted” where 85% or more of the crop produced in the U.S. is “bioengineered”—including canola, field corn, and soybeans. Foods are “not highly adopted” where less than 85% of the U.S. crop is bioengineered—including apples with non-browning cultivars, sweet corn, papaya, potato, and summer varieties of squash. The proposed rule provides a process by which the lists can be updated depending on changes in technology and food cultivation.

Disclosure Options

Except for certain exemptions (more on that below), if a food product appears on, or contains an ingredient on, either the “highly adopted” or “not highly adopted” list, regulated entities will be required to make a disclosure on the label of that food product or not make a disclosure if they have documented verification that the food is not a bioengineered food or that it does not contain a bioengineered food ingredient.

The proposed rule allows regulated entities to choose from at least three disclosure options for non-exempt foods: a text disclosure on a food label, a symbol disclosure, or an electronic link disclosure. The USDA is considering a text message disclosure option as well. Under this proposed option, the company would be required to include a statement on the food label directing the consumer to a number to text for more information about the food. The number must provide an immediate response with only the required text disclosure.

If a regulated entity uses a text disclosure on a food label, the disclosure requirement would vary depending on which list the food or food ingredient appear. For food products made from ingredients on the “highly adopted” list, the regulated entity would disclose that the food product “Contains a bioengineered food ingredient.” For food products made with ingredients on the “not highly adopted list,” USDA proposes to give regulated entities the discretion to use the disclosure “May contain a bioengineered food ingredient” instead.

For the symbol disclosure option, the USDA proposes three symbols for public comment (along with black-and-white versions of each).

For the electronic link disclosure option, the USDA proposes to allow regulated entities to include a link on food packaging that can be scanned by a smartphone, at which point the user’s smartphone will open a website containing the required disclosures. The USDA seeks comments on text statements that would accompany the digital link—for example, “Scan icon for food information.” Regulated entities that use digital link disclosures would also be required to include a telephone number on the food label that would allow consumers to call at any time of day and receive the required disclosure.

The possible text message disclosure option would allow regulated entities to provide a number on food packaging and an instruction to send a text message to that number “for more food information.” After sending a text message to that number, the consumer would receive a text message in response containing the required disclosure for that food product.

Entities responsible for disclosure would be required to maintain records necessary to substantiate compliance with the standards for individual disclosure options, including the type and wording of the disclosure used, and to substantiate the claim included in the disclosure or implied by the absence of a disclosure statement.

Exemptions from the Labeling Requirements

The proposed rule exempts a number of foods and food manufacturers from the labeling requirements. Exempted foods include animal products (e.g., meat or eggs) from animals that consume feed containing bioengineered ingredients; food certified as organic under the USDA’s national organic program; and food served in restaurants or similar retail food establishments, including cafeterias, food stands, and bars.

The USDA is weighing different options for two categories of additional exemptions: an exemption based on the relatively low level of bioengineered ingredients in a food product, and an exemption for small food manufacturers based on the manufacturers’ annual receipts. The USDA seeks public comment on the appropriate thresholds for these exemptions, and proposes several different options for consideration.

Proposed Compliance Dates

The USDA proposes a compliance deadline of January 1, 2020, with a delayed compliance date of January 1, 2021 for small food manufacturers. The USDA’s proposed deadlines for bioengineered food disclosures are intended to align with the Food & Drug Administration’s extension of the deadlines to comply with updated Nutrition Facts, Supplement Facts and Serving Size labeling requirements to the same dates.

Final Thoughts

The USDA’s statutory deadline to issue a final rule, July 29, 2018, is fast approaching. But it likely will not meet it because the proposed rule contains a number of unanswered questions, many relating to critical issues such as how the presence of “bioengineered” ingredients will be disclosed and which foods and food manufacturers will be exempted from the labeling requirements.

These unanswered questions also mean that the final rule is likely to be influenced significantly by public comments. Food manufacturers, retailers, consumers, industry groups, and other interested parties have an important opportunity to shape the final contours of the USDA’s bioengineered food labeling rules.

Seyfarth Shaw is pleased to announce The BioLoquitur Bulletin: Drugs Available in 2018 for Generic Competition, published by the Life Sciences team. The BioLoquitur Bulletin provides a brief overview of selected New Chemical Entities (NCE) that were approved by the FDA in the year 2014. While not every NCE will be a target for NCE-1 litigation, the Dissection Guide offers information about the drug products, indications, and Orange Book patents.

In calendar year 2014, the FDA’s Center for Drug Evaluation and Research (CDER) approved 41 novel new drugs as new molecular entities (NMEs) under New Drug Applications (NDAs) or as new therapeutic biologics under Biologics License Applications (BLAs). More than one-third of the novel new drugs approved in 2014 (17 of 41 or about 41%) were identified as First-in-Class and about 41% of the novel new drugs approved in 2014 (17 of 41) were approved to treat rare or “orphan” diseases.

CDER designated 41% as fast track, 22% as breakthrough therapies, 61% as priority review and 20% under FDA’s Accelerated Approval program. Further, a majority of the novel new drugs of 2014 (32 of 41, 78%) were approved on the “first cycle” of review, meaning without requests for additional information that would delay approval and lead to another cycle of review. See The Bulletin for more information.

Seyfarth’s Life Sciences team includes a multidisciplinary group of legal professionals with strong technical backgrounds in biology, biochemistry, organic chemistry, molecular biology, and pharmacology. Our team of experienced trial and appellate lawyers craft and execute comprehensive intellectual property strategies from initial drug development through trial and appeal.

How to Get Your Copy of The BioLoquitur Bulletin

Click here to download the pdf.

 

The Food and Drug Administration (FDA), as part of its Drug Competition Action Plan, published a draft guidance detailing good practices for the submission of ANDAs on January 3, 2018. The guidance highlights common, recurring deficiencies that may lead to a delay in the approval of an ANDA and makes recommendations to applicants on how to avoid such deficiencies. A typical ANDA requires an average of four review cycles before approval. The delay happens when ANDAs are submitted without all the information that the FDA needs to determine whether the ANDA meets FDA standards for approval, which leads to additional review cycles. Continue Reading Good ANDA Submission Practices: Summary of Draft Guidance

In a few short days, the United States will mark the eight-year anniversary of the Biologics Price Competition and Innovation Act (“BPCIA”). Signed into law on March 23, 2010, the BPCIA creates a regulatory pathway for the approval of biosimilar drugs in the United States and a mechanism, albeit voluntary, for resolving patent right disputes relating to the innovator biologic products.  Continue Reading “Rigged” Pricing, Contracting and Rebate “Schemes,” and Drug Pricing “Shell Games:” FDA Commissioner Scott Gottlieb Lets Loose on the U.S. Biosimilar Market While Offering Peek at New Policies

U.S. Food and Drug Administration (FDA) Commissioner, Dr. Scott Gottlieb, has made generic drugs and drug pricing an agency priority by emphasizing the critical value of generic drugs to public health. In 2017, 1027 total generic drugs were approved, which was the highest number of generic drugs approved in a single year.[1] Table 1 below illustrates 2017 approvals by month. Continue Reading FDA’s Office of Generic Drugs: 2017 Annual Report Highlights

In late December the FDA issued a new guidance, entitled “Best Practices for Communication Between IND Sponsors and FDA During Drug Development.” The purpose of the guidance is to “describe best practices and procedures for timely, transparent, and effective communications between investigational new drug application (IND) sponsors and FDA at critical junctures in drug development.” The hope is the guidance facilitates an earlier availability of safe, effective and high-quality drugs to the American public, including biosimilars.

The IND phase of drug development is the time during which human trials of investigational drugs are conducted. From the FDA’s perspective, the IND phase spans the time from the first IND-related submission (including a pre-IND or Biosimilar Initial Advisory (BIA) meeting request or an original IND) to the submission of a marketing application. The FDA engages in thousands of communication with drug sponsors during the IND phase. As such, the FDA’s guidance encourages efficient, consistent, clear and concise communications.

The new guidance particularly lays out and describes the following: the FDA’s philosophy regarding timely communications with IND sponsors as a core activity; the scope of appropriate interactions between review teams and IND sponsors; the types of advice that are appropriate for IND sponsors to seek from FDA; the expectations for the timing of FDA responses to IND sponsor inquiries; the best practices and communication methods to facilitate interactions with the FDA; and the expectations for appropriate methods of communication with the FDA.

At bottom, the FDA engages in thousands of communications with IND sponsors each year. Given the sheer volume of communications the FDA must review and respond to, facilitating a consistent, complete and concise communication protocol will assist the FDA in reviewing and providing timely and cogent feedback to the sponsors where appropriate. This, in turn, should result in greater efficiency during the drug development process to the benefit of the American public.

On December 7, 2017, the FDA announced three new policy documents geared toward advancing and properly overseeing innovative new digital health tools. The documents mark an acute recognition by the FDA that as consumers and health care providers increasingly use digital technologies as health tools to acquire information, the FDA’s policies must continue to encourage the development of such technologies.

Of the three new guidance documents, two are drafts and one is final. The guidances address the provisions of the 21st Century Cures Act and clarify where the FDA has a role in the promotion of digital health care.

The first guidance is titled “Clinical and Patient Decision Support Software” and addresses clinical decision support software (CDS). CDS technology assists health care providers in making decisions as to the course of treatment for a patient’s disease or condition. The FDA seeks to encourage software developers to create and expand CDS functionality in treating old and new diseases. The guidance identifies which types of CDS do not qualify as a “medical device” and thus do not require FDA regulation, namely, CDS that permits the health care provider to independently review the basis of the recommendation for treatment.

The second guidance addresses the FDA’s interpretation of other types of software that are similarly no longer considered medical devices, titled “Changes to Existing Medical Software Policies Resulting from Section 3060 of the 21st Century Cures Act.” In particular, this guidance sets out that digital health technologies such as mobile apps that are used by consumers to log, record, track, evaluate and make decisions on a healthy lifestyle, like dietary logs, meal planners, or activity trackers, fall outside the scope of FDA regulations.

Lastly, the FDA issued a final guidance, “Software as a Medical Device: Clinical Evaluation,” expanding the draft issued in October 2016. The guidance establishes and harmonizes global principles for evaluating the safety, efficacy and performance of Software as a Medical Device, based upon the overall risk of the product.

The three guidances issued last week seek to continue to clarify the FDA’s role and oversight in digital health technologies. As the ever-changing field of digital health technology expands, so too will the FDA’s efforts to encourage innovators to create and expand such technology.

The ability to facilitate the regeneration of parts of the human body is “no longer the stuff of science fiction” according to FDA Commissioner Scott Gottlieb.[i] According to Commissioner Gottlieb, the cell based therapies and their use in regenerative medicine is one of the most promising fields of science already producing “improbable advances.” At the current early stages of development, deceptive claims from unscrupulous actors risks “jeopardizing the legitimacy and advancement of the entire field.” In order to curb such deception while simultaneously providing a clear and efficient path for product developers, the FDA has recently published a suite of four new guidance documents related to their regenerative medicine policy framework.

These four guidance documents represent a broad policy framework by the FDA building upon the framework put into effect in 2005. In its never ending battle to ensure the safety and efficacy of medical products while simultaneously supporting innovation, the FDA’s new approach will undoubtedly entail additional requirements on those innovators in the regenerative medicine field. It is important to review the guidance documents to ensure compliance with the FDA, but also to take advantage of the various opportunities for approval for those medicines and products that meet certain criteria. For this purpose, below is a brief summary of what the guidance documents include.

As guidance documents, the information provided does not create legally enforceable responsibilities, but rather they provide a glimpse into how the FDA is currently thinking and how the FDA will likely apply the existing laws and regulations that govern regenerative medicine products. Two of the documents are final guidance documents now in effect with the remaining two documents in draft form allowing the public to provide their comments.

Final guidance documents

The first guidance document titled “Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception”[ii] provides clarity on when cell and tissue-based products would be excepted from the current regulations if they are removed from and implanted into the same individual during the same surgical procedure and remain in their original form.

The second guidance document titled “Regulatory Considerations for Human, Cell, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use”[iii] clarifies how the FDA interprets the regulatory definitions for “minimal manipulation” and “homologous use.” This guidance is particularly helpful in that these concepts establish the legal threshold for when a particular product is subject to the FDA’s premarket approval requirements. In light of the how this new interpretation will effect manufacturers, healthcare providers, the FDA plans to exercise ‘enforcement discretion’ to those products that do not pose a potential significant safety concern for 36 months.

Draft guidance documents

The first draft guidance document titled “Evaluation of Devices Used with Regenerative Medicine Advanced Therapies”[iv] attempts to clarify how the FDA will evaluate devices referred to as “regenerative medicine advanced therapies” or “RMATs” in accordance with the regenerative medicine provisions in the 21st Century Cures Act. These devices include medical devices used in the recovery, isolation, or delivery of RMATs. It is the goal of the FDA to simplify and streamline the application of the regulatory requirements of RMATs.

The second draft guidance document titled “Expedited Programs for Regenerative Medicine Therapies for Serious Conditions”[v] describes, unsurprisingly, various expedited programs to sponsors of RMATs. In addition, the guidance also describes the new RMAT designation process to be used.

The two draft guidance documents were posted to the Federal Register on November 17, 2017, with a comment period ending February 15, 2018. There is ample time for interested parties to assist the FDA in finalizing the draft guidance documents by submitting a comment by the February 15, 2018, deadline.

These guidance documents may provide new opportunities or new requirements for those operating in the field of regenerative medicines. They should be reviewed to ensure compliance with existing laws and regulations while also looking to take advantage of the programs to accelerate FDA approval.


[i] “Statement from FDA Commissioner Scott Gottlieb, M.D. on FDA’s comprehensive new policy approach to facilitating the development of innovative regenerative medicine products to improve human health” posted November 16, 2017, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585342.htm; see also, “FDA announces comprehensive regenerative medicine policy framework” posted November 16, 2017, available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm585345.htm.

[ii]  Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/UCM419926.pdf.

[iii] Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585403.pdf.

[iv] Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585417.pdf.

[v] Available at https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/UCM585414.pdf.

This article provides a summary of the draft guidance[1] released by the FDA to assist applicants in determining which one of the abbreviated approval pathways under the Federal Food, Drug and Cosmetic Act (FD&C Act) is appropriate for the submission of a marketing application to the FDA. The draft guidance was released on October 13, 2017, for which comments are due by December 12, 2017.

The guidance expanded on the different pathways for obtaining approval of new drug applications (NDAs) and abbreviated new drug applications (ANDAs), which became available with the passage of the Hatch-Waxman Amendments. In addition, the guidance discussed the regulatory and scientific considerations for determining whether to file an ANDA or a 505(b)(2) Application.

Abbreviated Approval Pathways:

1. Stand-Alone NDA Application:

  • Submitted under section 505(b)(1) and approved under section 505(c) of the FD&C Act and contains “full reports of investigations of safety and effectiveness that were conducted by or for the applicant or for which the applicant has a right of reference or use.”

The guidance did not discuss stand-alone NDAs. It focused on those applications that can be submitted as ANDAs under section 505(j) of the FD&C Act, petitioned ANDAs under 505(j)(2)(c) of the FD&C Act, or NDAs pursuant to section 505(b)(2) of the FD&C Act.

2. 505(b)(2) Application:

  • Submitted under § 505(b)(1) and approved under § 505(c) of the FD&C Act, and contains “full reports of investigations of safety and effectiveness, where at least some of the information required for approval comes from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference or use.”
  • May rely on the FDA’s safety and/or efficacy findings for a listed drug only to the extent that the proposed product of the 505(b)(2) application shares characteristics in common with the listed drug.
    • NOTE: A drug product in a 505(b)(2) application will not necessarily be treated as bioequivalent or therapeutically equivalent to the listed drug(s) relied upon. The applicant is expected to establish a bridge (e.g., by using comparative bioavailability data) between the proposed drug product and each listed drug that the applicant seeks to rely upon to demonstrate that reliance on the listed drug is scientifically justified.
  • Must include sufficient data to support the differences, to the extent that the listed drug and the proposed § 505(b)(2) drug differ.

3. ANDAs

  • Submitted and approved under section 505(j) of the FD&C Act.
  • Must establish that the proposed generic product (1) is the same as the reference listed drug (RLD) with respect to the active ingredient(s), dosage form, route of administration, strength, previously approved conditions of use, and labeling (with permissible differences), and (2) is bioequivalent to the RLD.
  • May not be submitted if studies are necessary to establish the safety and effectiveness of the proposed product because it relies on FDA’s finding of safety and effectiveness for an RLD.

4. Petitioned ANDAs:

  • Submitted and approved under § 505(j) of the FD&C Act.
  • A type of ANDA for a drug product that differs from the RLD in its dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient), and for which, in response to a petition under § 505(j)(2)(c) of the FD&C Act, the FDA has determined that safety and efficacy studies are not necessary for the proposed drug product.

Regulatory Considerations for ANDAs and 505(b)(2) Applications:

1. Duplicates:

  • The FDA generally will refuse a 505(b)(2) application for a drug that is a duplicate of a listed drug and eligible for approval under § 505(j) of the FD&C Act.
    • However, if FDA approves a duplicate product after a § 505(b)(2) application is submitted, but before the § 505(b)(2) application is approved, the 505(b)(2) application would remain eligible for approval.

2. Petitioned ANDAs:

  • An applicant may submit a petition under § 505(j)(2)(c) of the FD&C Act (a suitability petition) to FDA requesting permission to submit an ANDA for a generic drug product that differs from an RLD in its route of administration, dosage form, or strength or that has one different active ingredient in a fixed-combination drug product.
  • A suitability petition will generally be approved unless (1) the FDA determines that the safety and effectiveness of the proposed change from the RLD cannot be adequately evaluated without data from investigations that exceed what may be required for an ANDA, or (2) the petition is for a drug product for which a pharmaceutical equivalent has been approved in an NDA.

3. Bundling:

  • An applicant may seek approval for multiple drug products containing thesame active ingredient(s) when some of these products would qualify for approval under the section 505(j) pathway and some would qualify for approval under the 505(b)(2) pathway.
  • FDA has permitted an applicant to submit a single “bundled” 505(b)(2) application forall such multiple drug products.

Scientific Considerations for ANDAs and § 505(b)(2) Applications:

1. Limited Confirmatory Studies:

  • If the safety or effectiveness of a proposed drug product must be established by investigations, then an ANDA application is not appropriate.
  • However, data from limited confirmatory testing to show that the characteristics that make the proposed drug product different from the listed drug do not alter its safety and effectiveness may be submitted in an ANDA.

2. Active Ingredient Sameness Evaluation:

  • “If the active ingredient in an applicant’s proposed drug product cannot be demonstrated to be the same as the active ingredient in the RLD by using the information and data that may be submitted in connection with an ANDA, the drug product should not be submitted for approval in an ANDA.”
  • In situations where current limitations of scientific understanding and technology may preclude approval of an ANDA with the data permitted for submission in an ANDA, FDA may be able to receive, review and approve ANDAs as the scientific understanding and technology evolve.

3. Intentional Differences Between the Proposed Drug Product and an RLD:

Differences in Formulation:

  • An ANDA must include information regarding the identity and quantity of all active and inactive ingredients of the proposed drug product and a characterization of any permitted differences between the formulations of the proposed drug product and the RLD, along with a justification demonstrating that the safety and effectiveness of the proposed drug product is not adversely affected by these differences. If the proposed drug product contains changes to its formulation that are not permissible in an ANDA, the applicant should consider submitting a 505(b)(2) application.

Differences in Bioequivalence and/or Bioavailability Differences:

  • An ANDA must contain information to show that the proposed drug product is bioequivalent to the RLD, such as (i) the rate and extent of absorption of the proposed drug do not show a significant difference from that of the RLD when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses.
    • NOTE: “[(w]here there is an intentional difference in rate (e.g., in certain extended-release dosage forms), certain pharmaceutical equivalents or alternatives may be considered bioequivalent if there is no significant difference in the extent to which the active ingredient or moiety from each product becomes available at the site of drug action.”
  • An application for a proposed drug product where the rate and/or extent of absorption exceed, or are otherwise different from, the 505(j) standards for bioequivalence may be submitted under the 505(b)(2) pathway and may require studies to show the safety and efficacy of the proposed product at the different rate and/or extent of delivery.  However, the FDA generally will not accept a 505(b)(2) application for a drug product where the only difference from a listed drug is that (1) the extent to, or (2) the rate at, which its active ingredient is absorbed or otherwise made available at the site of action isless than that of the RLD.

Differences in Conditions of Use:

  • A § 505(j) application must include a statement that the conditions of use prescribed, recommended, or suggested in the labeling for the proposed drug product have been previously approved for the RLD. The application cannot be approved as an ANDA if the proposed drug product has added a new indication. However, the FDA will not refuse to approve an ANDA whose proposed labeling excludes conditions of use approved for the RLD because of patents or exclusivity.

4. Other Differences:

  • Drug products that differ considerably from the RLD are generally not candidates for the § 505(j) pathway. In assessing whether differences between a proposed generic drug product and the RLD would necessitate additional data or information to establish the safety or efficacy of the proposed drug product, FDA will examine the individual differences between the products and the combined effects of those differences.

 


[1] https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM579751.pdf