Spotlight Q&A: A Deep Dive Into Generics and ANDA Filings With Cardinal Health Regulatory Sciences

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OVERVIEW: Yin Lai, PhD, MSc, RAC is Director of Chemistry, Manufacturing and Controls at Cardinal Health Regulatory Sciences. Andy Trammel, PhD is Principal Scientist, Chemistry, Manufacturing and Controls at Cardinal Health Regulatory Sciences. These two experts will discuss generics, how they differ from innovator drugs, and the requirements necessary for regulatory approval in the United States.

Yin Lai, Director of Chemistry, Manufacturing and Controls

What are generic drugs, how do they differ from innovator brand-name drugs, and what regulatory pathways (including the Abbreviated New Drug Application (ANDA)) guide FDA approval? 

Generic drugs are available as a result of the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Amendments. The enactment of this act established a regulatory pathway for review and approval of a generic drug, which is a copy of an innovator drug and comparable to the innovator drug in terms of active pharmaceutical ingredient, dosage form, strength, route of administration, quality, performance characteristics, and intended use. The regulatory pathway established for review and approval of generic drugs is by an Abbreviated New Drug Application (ANDA), which is based on 505(j) of the Food, Drug & Cosmetic Act, FD&C Act.

New innovator drugs are typically protected from competition by patents and by exclusivity periods. However, once these market protections expire, then generics can be approved for use as a substitute for the innovator.

What are the key differences between 505(b)(1) New Drug Application (NDA) (innovator) and ANDA 505(j) pathways for drug approval?

505(b)(1) NDA is the regulatory pathway for review and approval of new, innovator drugs. Innovator drug sponsors generally need to provide full data in terms of safety and efficacy to support the submission and approval of the NDA. Data support include chemistry, manufacturing, controls, microbiology, product labeling, laboratory and animal studies, and clinical studies.

ANDA is an abbreviated application relative to the 505(b)(1) NDA because the ANDA sponsor generally will not need to perform animal/preclinical studies and clinical studies to demonstrate safety and effectiveness of the generic drug.  Generic drug sponsors rely upon the safety and efficacy that has been demonstrated by the reference listed drug (RLD), which is the innovator drug listed in Orange Book.  Instead, generic sponsors  should demonstrate the generic drug is bioequivalent to the innovator drug, the RLD.  This means that the generic drug generally need to show no significant differences in terms of rate and extent of absorption as the RLD.  Typically, the ANDA sponsor will need to provide chemistry, manufacturing, controls, microbiology, facilities inspection, product labeling, and most importantly bioequivalence studies.

What is GDUFA and how does it impact generic drug development?

Generic Drug User Fee Amendments (GDUFA) enabled the FDA to collect user fees to support generic drug review and related activities. In return, FDA agreed to meet certain performance goals such as setting goal dates for generic drug applications and supplements review. In September 2022, the FDA User Fee Reauthorization Act of 2022, which includes reauthorization of GDUFA through September 2027 (GDUFA III) was signed into law. This is the most current GDUFA in effect for 2024. GDUFA has accelerated generic drug entry into the US market.

What is bioequivalence and what criteria according to FDA must a generic drug meet to demonstrate bioequivalence for a brand-name drug in an ANDA submission?

Bioequivalence demonstrates that the generic drug and RLD are the same or do not demonstrate significant differences in terms of rate and extent of drug absorption when administered at the same dose under similar conditions. Product Specific Guidances (PSG) are available for many drugs that guide the sponsor in the design and execution of bioequivalence studies. The ANDA sponsor can propose alternative approaches/studies deemed adequate by FDA to demonstrate bioequivalence.

Andy Trammel, PhD, Principal Scientist, Chemistry, Manufacturing and Controls

How do patents and exclusivity rights, e.g. 180-day exclusivity for first generic applicants, impact the timing of generic drug submissions, approvals, and market entry?

The term of a new patent is generally about 20 years from the date on which the application for the patent was filed in the United States.  Also, typically a patent is filed and approved early in the development process and so many of the 20 years are used before the product is approved.  Exclusivity on the other hand refers to prohibition or delay of approval of a product or entrance into the commercial market.  There are various exclusivities that a drug sponsor can apply if the generic drug satisfies the requirements.  For example, the first generic drug is eligible for 180-day exclusivity.  Exclusivities available for generics include Pediatric Exclusivity (PED), Patent Challenge (PC) and Competitive Generic Therapy (CGT).

The generic sponsor generally need to provide patent certification in the ANDA application.  Based on the patent challenge condition, an ANDA may be delayed.  For example, if the ANDA sponsor provides Paragraph IV patent certification, notifying the RLD holder challenging the patent and the RLD holder launches patent infringement action within 45 days of the notice to defend its patent, then a 30-month stay will be invoked.  This will likely delay the approval of the generic drug to the market pending on the status of the litigation.

However, for many older drugs, patents (and exclusivity issues) have long since expired.

What is the typical total time of development and major milestones leading up to submission of the ANDA?

Based on GDUFA III goal dates, typically, standard review of an original ANDA will generally take 10 months from the filling date whereas priority original ANDA review will take about 8 months from the filling date.

While the time for development and approval of an ANDA overall is shorter than an NDA, the approval process is still lengthy, depending on your point of view and generally requires the sponsor of the ANDA to develop a long-term view over the whole process.  Working backwards, from receipt of the initial ANDA to approval (for a first review approval) is 10 months based on the requirements in the current GDUFA.

The ANDA should be submitted with at least 6 months stability of the final dosage form that is representative of the commercial drug.  This can often take 8-12 months to plan and gather the data for stability alone.

The development time before these critical stability batches is studied can be around 1 year in addition to the times above.  A bioequivalence study can add time as well.  There are many variables, of course, but a 1+ year’s time is common considering all the decisions and studies that must be performed.

The above times are quite variable but it can be seen that a 3-year time window is likely from start of studies to approval, and this is dependent on no significant surprises or delays in development such as issues with the bioequivalence study, or even review issues by the FDA.  Many studies can be done in parallel but with associated risk.

What are “branded generic” and “authorized generics” and how do they differ from typical generic drugs? 

An authorized generic is the same drug as the innovator drug but marketed without using the brand name on its label by the innovator company or other drug company with permission/agreement from the innovator company.  The authorized generics are generally sold at a lower price compared to the innovator drug.  This is a strategy for the innovator company to capture some of the generic drug market. The innovator drug sponsor should notify FDA if they intend to market an authorized generic.  The innovator drug company can market both the innovator drug and authorized generic at the same time.  The authorized generic drug is not listed in the Orange Book; however, the authorized generic drug list is provided on the FDA website.  On the other hand, both branded generic and unbranded generic drugs must go through the ANDA regulatory pathway and may have minor differences compared to the RLD such as inactive ingredients.  If a generic drug is given a brand name, then this is typically called the branded generic.  The authorized generic usually costs less than the innovator drug but generally more than the branded and unbranded generic drugs.

What post-approval obligations do generic drug manufacturers have regarding surveillance, pharmacovigilance, and adverse event reporting to FDA?

The generic drug holder typically has similar post-marketing responsibilities as the innovator drug holder. These responsibilities may include but are not limited to safety reports, post-approval reports such as annual reports, any changes to ANDA ownership, any changes to ANDA, post-marketing requirements (PMR), post-marketing commitments (PMC), labeling changes, adverse event reporting, field alert reports and special reports notifying FDA on drug shortage or discontinuation of manufacturing. In addition, the ANDA holder should monitor Orange Book information closely because the holder will need to make necessary changes and regulatory submissions to the ANDA based on the changes to the RLD made by the innovator drug NDA holder, for example, a labeling change.

How does the FDA regulate quality and consistency of generic drugs?

FDA generally regulates quality and consistency of generic drugs through two processes, namely pre-approval and post-marketing processes.  For pre-approval, FDA will review the data submitted for an ANDA marketing application.  The ANDA data submitted include quality and manufacturing data, pharmaceutical equivalence (PE) to RLD in terms of API, dosage form, strength, route of administration, cGMP and condition of use, and bioequivalence (BE) to RLD.  As previously mentioned, BE typically evaluates the rate and extent of generic drug absorption relative of that of the RLDs.  It ensures that the generic drug perform similarly physiologically to the RLD.  The FDA will review the totality of the data and evidence in support of ANDA for approval.

For post-marketing, the FDA will monitor and evaluate post-marketing reports to evaluate any early signs of quality and safety issues/trends.  This includes safety surveillance, review of published literature, direct contact with patients and healthcare professionals, drug manufacturers reports, FDA database, reports from other regulatory agencies, and past experience of certain quality issues for certain class of drugs. Post-approval safety surveillance monitoring and post-approval reports ensure generic drug safety and quality.

What are some of the common issues with obtaining ANDA approval and what are some of the regulatory tools that FDA provides to avoid such issues?

There many common issues found during the review of ANDA. Major issues may include but are not limited to inadequate stability data, deficiencies in the sameness assessments, inadequate dissolution studies, bioequivalence studies, impurities assessment, control strategies, and basis of submission.

In light of the common issues observed during ANDA review, FDA has provided multiple pathways and tools to help with ANDA sponsors. The tools provided include but are not limited to different types of meeting and interaction opportunities (controlled correspondences, product development meeting, pre-submission meeting, etc.), pilot programs, regulatory guidance including Product Specific Guidance (PSG), Orange Book, multiple databases, conferences, workshops, webinars, townhalls, and training courses.

What fees are required for an ANDA submission and review?

The fee for an ANDA application is $252,453.  For firms with approved ANDAs a GDUFA program fee is assessed each year based on the number of approved ANDAs the sponsor owns.  This fee ranges from $1,729,629, to $172,963 respectively for fiscal year 2024.  There are also other fees regarding facilities and other aspects of maintaining the application.


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This information is provided for educational purposes only. Cardinal Health is not responsible for any use of the information contained herein, or any implemented recommendations or results therefrom. The opinions and recommendations expressed are solely those of the author and not necessarily those of Cardinal Health, or its subsidiaries or affiliates.

 

 

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