What’s New on FDA Generic Drugs Forum 2021?

Once a year, the Generic Drugs Forum was held on April 28 - 29, 2021 by the FDA Office of Generic Drugs (OGD). ⁽¹⁾ OGD is the world leader in the science and regulation of generic drugs, serving an essential role in advancing FDA’s public health mission, and ensuring high-quality, affordable generic drugs are available to the American public.

There was a lot of valuable information presented at this 2-day event， which offered practical advice, case studies, and a deep dive into the Abbreviated New Drug Application (ANDA) review process ^(2), which is an excellent opportunity to reach the largest assemblage of participants from the Generic Drugs Community and discussed directly with FDA OGD officials. 

This forum is also particular helpful for the consultants, regulatory affairs professionals, or contractors with an emphasis on those who plan to submit an ANDA or are in the process of submitting an ANDA, involved in generic drug development, work on bioequivalence, stability, dissolution and impurity testing and prepare regulatory submissions. There were numerous presentations focused on various aspects from pre-ANDA, drug development, post-marketing and global generic drug affairs program support for the generic drug program during the sessions.

I hereby would like to share some highlights of the Generic Drug Forum 2021 with our colleagues. As one of clean room suppliers, Pharmasource is willing to share information with you.

First of all, FDA OGD officials provided a significant amount of review information and suggestions for success in ANDA submission and approval during the COVID-19 pandemic. Some presenters provided their experiences and views on other issues, including the importance of OGD findings on data integrity in clinical study data, bioequivalence data, pharmacokinetic data, and toxicology data in GLP and non-GLP studies.

Secondly, like most organizations around the world, the FDA OGD experienced unprecedented and unique challenges during the COVID-19 public health emergency. FDA OGD quickly pivoted to prioritizing the assessment of generic drug submissions for products that could help address COVID-19 as the top priority. In addition to FDA emergency response to the COVID-19 pandemic, OGD and the entire generic drug program maintained FDA’s rigorous standards for evaluating non-COVID-19 products based on quality data and sound science.

Thirdly, OGD identified and pursued effective tools and strategies to aid in the fight against COVID-19 pandemic and created a new system for identifying generic drugs that are critical to the treatment of patients with COVID-19 and subsequently took regulatory and scientific action to accelerate review of those products. This new system included establishing the infrastructure to rapidly complete tasks and resolve review issues in support of taking timely actions on critical generic drugs used in the pandemic.

OGD also worked diligently to support manufacturers of approved generic drugs who needed to make changes to manufacturing processes or facilities to address disruptions caused by the COVID-19. These products included antibiotics, sedatives used in ventilated patients, anticoagulants, and pulmonary medications, among others. 

As Director of Office of Generic Drugs (OGD), Dr. Sally Choe showed that OGD has prioritized assessment of over 50 ANDAs, and more than 800 supplemental applications were approved for drug products used to treat patients with COVID-19  pandemic in FY 2021. Dr. Choe also noted that, in FY2020 alone, 32 new or revised product-specific guidances (PSGs) introduced an in vitro option to demonstrate bioequivalence.  She emphasized such options provided a lower regulatory hurdle while at the same time provides the assurance that generic drug products are indeed bioequivalent. In the prescription drug market, OGD helped increase competition by approving or tentatively approving 948 ANDAs, including 72 first generics approvals, 35 generics with the Competitive Generic Therapy (CGT) designation, 121 pre-ANDA meeting requests received, 3,711 controlled correspondence, and 1,952 complete response letters issued. ⁽²⁾

Fourthly, OGD officials provided further information on the pre-ANDA program and gave a comprehensive review of the pre-ANDA meeting program ⁽³⁾ and meetings for complex products.  The Pre-ANDA Program is a valuable information resource for generic drug applicants. The program features product development assistance and pre-submission and mid-review cycle meetings to help clarify regulatory expectations early in product development and during application review.  It is very important to know that the pharmaceutical industry can now request FDA Pre-ANDA Meetings for Complex Generic Drug Products via CDER Direct NextGen Collaboration Portal ⁽⁴⁾ to assist ANDA applicants  and prospective applicants before they submit an ANDA to the FDA.

It was noted that, of the 44 pre-ANDA requests for non-complex products submitted, 9 or 20% were granted during FY 2021.  However, for complex products, of the 309 received, 233 or 75% were granted by OGD (non-granted requests were either denied or withdrawn).  For instance, several complex ANDA products were approved including Glucagon for injection, ⁽⁵⁾ Ferumoxytol injection, ⁽⁶⁾ Imiquimod cream, ⁽⁷⁾ Linaclotide capsules,(8) and Loteprednol etabonate ophthalmic gel. ⁽⁹⁾ However, it was  found that the two most common reasons for denial were incomplete meeting packages or FDA’s instruction to submit as a controlled correspondence.  Please be aware that examples in the form of case studies were provided to outline deny or grant decisions with many helpful tips provided.

Fifthly, as we know that post-marketing drug safety issues with generics are usually not significant as they present a profile very similar to their brand name counterparts, but, as the pharmacovigilance presentation noted, there may be differences seen in quality attributes when a new generic is first introduced to the market, especially if there are any differences in drug-device combination products. Some of the past experiences with quality issues including unusual odor, taste, smell, or texture, tablets breaking apart, scored tablets breaking unevenly or crumbling when split, precipitates in oral liquids and injectables, container/closure issues, eyedrop safety seals falling off and extended-release products not lasting through the day and et al.

During the forum, OGD officials also provided a few examples of where such activity can provide early notification of either the lack of potential quality and safety issue or identify a significant issue. For instance, the Advair and generic Wixela Inhub that had minor differences in the dry-powder inhaler showed no quality or safety issues after initial monitoring. However, the allowed difference in the Copaxone and generic autoinjector showed that the generic autoinjector had a more frequent issue with bent or broken needles relative to brand. Another example, the Proair HFA albuterol inhaler was the brand name product, the difference allowed and approved in the generic inhaler showed an unexpected safety signal after approval on February 24, 2020, ⁽¹⁰⁾ when reports of inhaler clogging began to be reported.  Furthermore, In August 2020, the generic manufacturer and distributor discontinued manufacture and distribution and recalled the product ⁽¹¹⁾ to the consumer level.

Sixthly, the forum discussed Emerging Technologies for manufacturing and testing provided a challenge to the pharmaceutical industry and the FDA but the rewards can be improved efficiency in manufacturing and cost-saving to the industry.  Various novel manufacturing techniques, such as 3D printing, end-to-end manufacturing, continuous manufacturing, and continuous aseptic spray drying, were also discussed. While the FDA knows many of the emerging technologies, some are brand spanking new and the FDA will have to learn along with the applicant.

Finally, the forum also talked about the market of generic drugs. According to the market analysis report, the International Generic Drug market ⁽¹²⁾ is expected to reach approximately 380.60 billion USD by 2021, growing at a CAGR of about 10.8 % between 2016 and 2021.  It was considered that the market of a generic drug is mainly driven by the factors such as cost-effectiveness and 135 billion worth patented drugs expiry and Government initiatives have given it a competitive lead over the branded drugs in the market in 2020 which can drive generic drug market into profits.

In particular, North America is a beholder of the largest share in the generic drug market, 89% of the prescribed drugs are generic and the demand is high for generic drugs in the US. However, in the Asia Pacific region, India and China dominated the generic drug market in volume, total Indian generic drugs market was around 21 billion USD in the year 2015 mainly due to the Indian companies getting international regulatory approvals like U.S FDA, MHRA.UK, TGA Australia, and MCC South Africa. Brazil was the largest generic market in Latin America, it is due to the sale of generic medicine was accounted for 23% and will remain to be dominant in the forecast period due to high demand and increasing development in the pharmaceutical sector. Europe is observed to show significant growth in the generic drug market as a result of the prevalence of chronic diseases and government support.

Today, the generic drug program is stronger than ever, and FDA OGD continues to take timely actions on COVID-19 and non-COVID-19 related ANDAs. That is good news for Americans. We expect the next FDA Generic Drug Forum 2022 with more breakthroughs.

References

1https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/office-generic-drugs

2https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/abbreviated-new-drug-application-anda-forms-and-submission-requirements

3(https://www.fda.gov/drugs/generic-drugs/pre-anda-program

4(https://www.fda.gov/media/107926/download

5https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-drug-used-treat-severe-hypoglycemia

6https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-strengthens-warnings-and-changes-prescribing-instructions-decrease

7https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/20723s11s12lbl.pdf

8https://www.fda.gov/media/83975/download

9Loteprednol=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202872_lotemax_toc.cfm

10https://www.fda.gov/news-events/press-announcements/fda-approves-first-generic-proair-hfa

11https://www.drugs.com/fda-alerts/109-2464.html

12https://www.databridgemarketresearch.com/reports/global-gener

About the Author

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.