GDFUA II ANDA (Abbreviated New Drug Application) Review Target of 8-10 Months should be a Cause of Concern

Understanding what it takes to file and get approval of any ANDA from US FDA is a great question and the answers are enlightening.

Practical impact of GDUFA II is that generic drug sponsors can expect to have their ANDAs reviewed and responded to within ten months of submission. If the review does not result in approval, the sponsor will receive a Complete Response Letter (CRL) which compiles a list of major issues the Agency has found with the application. The sponsor must rectify each deficiency before resubmitting the amended ANDA for another review cycle ⁽¹⁾. Word “review” does not mean “approval” and that can mean that the generic drug approval can still be wandering in halls of FDA. Based on this one has to wonder what is the purpose of the exercise. This is frightening and can make us all wonder “can US react to national security challenges posed by drug shortages and affordability”.  

I tried to find out how much real time it takes to get an ANDA approved. I was confident that someone at FDA can give an answer. Unfortunately I did not succeed. That in itself is a sad story. It is probably less painful to walk over bed of hot coals than spend time trying to get answer the subject question. No pun intended. There is no financial relationship with any for profit or non-profit organization.

I tried to find a flow diagram that will tell me/us a simple pathway and time gap between events. Unfortunately, I could not. Using testimony FDA documentation and suggested pathway, I have tried to create a simple schematic Figure 1^{(2,3,4,5, 6)}.  

GDUFA related information repeatedly suggest that ANDA would be reviewed in 8-10 months but does not give the total time it takes to get ANDA approved. Not having an example of average time it takes an applicant to get an approval is not very comforting. With this uncertainty I wonder can how bureaucracy of GDUFA instill competition in generic drugs, make drugs affordable and bring manufacturing jobs to US ⁽⁷⁾. Additional question can be “can FDA address US national security issues to alleviate dependence of generic drugs on other countries”. Based on published information, many will have serious doubts. 

Figure 1: ANDA Time Line

Review of following references each reader can draw their own conclusions. Testimony ⁽³⁾ of Directors of CDER, CBER, and CDAH, - Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research; Peter Marks, M.D., Ph.D., Director, Center for Biologics Evaluation and Research; Jeffrey Shuren, M.D., J.D., Director, Center for Devices and Radiological Health, Food and Drug Administration, U.S. Department of Health and Human Services (HHS) Figure 4 highlights first cycle approvals but does not give the actual numbers and the time period, a critical element. Figure 3 ⁽³⁾ shares relative number of meetings held. That clearly suggests that FDA has not clearly stated what it needs to get ANDA approved. 

Figure 8 in reference ⁽³⁾ touts number 835 ANDAs (approvals and tentative approvals) but does not reveal how much total time they took. Number for 2016 approvals is high. Question “were the numbers coincidentally stacked for 2016?”. Proof of the pudding is how many approvals are done in 90 days from the date of ANDA filing. This should the new normal ^{(5, 6, 7, 8)} we should expect. All kinds of numbers have been shared in this testimony ⁽³⁾ but the question is do they have any relevance when it comes getting the products to the patients by reducing time from ANDA application filing to their approval. One could call this busy work or self-appreciation. Essentially FDA has enslaved the pharmaceutical industry to dictate what and how of review and approvals. They even tell industry which methodologies and technologies they should use when they have not produced any product. 

GDUFA documents talk about application review time but no one shares or talks about how much real time (months) it takes from the day application arrives at FDA to get the review completed and application approved. That is a hidden secret and my conjecture is that no one has the real answer. ANDA approval time is most crucial and valuable answer as it influences availability and affordability of generic drugs.

Considerable effort was made trying to find out if there is a simple map (similar to Figure 1) for ANDA filings and approvals which will show ANDA filers do’s and don’ts of filing. Except for a simple road map one finds overwhelming volume of paper work one has to follow for any submission, try to master but still fail. 

The paper work and the shear bureaucracy for filing ANDA and for that matter NDAs also will essentially enslave every company. My conjecture is that as structured presently there is no single reviewer at FDA who knows what makes an application complete and is necessary for ANDA approval. Instead of companies having a template and telling companies what FDA needs to file/approve an ANDA each company’s application is reviewed by multitude and that is like being fitted by many to get a tailormade suit that needs repeated alterations.  

If all the referenced documents ^{(4, 5, 6,11, 12)} are printed and reviewed, it will take an army of chemists, chemical engineers, outside consultants and lawyers to figure out what all is needed for ANDA application approval. Poor chemist and chemical engineer who developed, designed and commercialized a process to produce quality product from the get go has no say in the exercise. They mastered their process and methods to create a quality product all the time is critiqued and subjected to second guesses and torture. They are being told to exercise QbD (quality by design), which they do. However, the regulators who create an approval pathway and should be model of QbD, believe in QbA (quality by analysis/aggravation) thorough pre, middle and post mortem meetings to review/approve every submission. I wonder how much hands-on experience reviewers have in process development, design, commercialization and managing any drug API manufacturing or their formulation.      

If FDA had template/s that can be used by companies, ANDA filing and review process ^(7,8,9,10) could be smoothed out to minimize approval time. They could be used to simplify NDA approval time also. Such simplification is necessary for self-reliance and manufacturing bringing jobs back to the United States to relieve its dependency on others specially with incentive of 30 day approval ⁽⁵⁾.

Let us hope that the ANDA related meetings with FDA are not a fertile ground for data manipulation that rear their ugly head during onsite inspections resulting in 483 citations ⁽¹³⁾ which are worthless as they have no impact on company. 

Prolonged ANDA review and approval processes have to be stopped as such adventures increase generic prices, reduce competition and put The United States strategically in a very vulnerable position and dependent on others ⁽⁷⁾. In addition, delays of months increase cost of drugs which is passed to patients. This is unacceptable. Question to FDA and the US Government is “Is the current vulnerability acceptable?” Most will say NO. What do you think? 

Girish Malhotra, PE

EPCOT International

1. How GDUFA II Impacts the Timing & Approval Process for Generic Drug Sponsors, Weinberg Group, Accessed March 23, 2020
2. Pre ANDA Program, Accessed March 23, 2020
3. Prescription Drug User Fee Act Reauthorization (PDUFA VI), Medical Device User Fee Act Reauthorization (MDUFA IV), Generic Drug User Fee Act Reauthorization (GDUFA II), Biosimilar User Fee Act Reauthorization (BsUFA II) Accessed November 25, 2018
4. Sherwood, Edward, GDUFA II Training - Goals October 25, 2017
5. Sherwood, Edward, Sansone, Vincent: FDA’s Generic Drug Program Offers Assistance, Resources For ANDA Applicants Pharmaexec.com, November 5, 2019, Accessed March 23, 2020
6. Sansone, Vincent: GDUFA II Performance Goals, FDA.gov, Accessed March 23, 2020
7. Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020
8. Malhotra, Girish: Can the Review and Approval Process for ANDA at US FDA be Reduced from Ten Months to Three Months?Profitability through Simplicity, http://bit.ly/33SiqHS  March 25, 2017
9. Malhotra, Girish: http://bit.ly/31ALUcu What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2018
10. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability: Profitability through Simplicity, December 6, 2019
11.  Abbreviated New Drug Application (ANDA), Accessed March 23, 2020
12. Filing Review of Abbreviated New Drug Applications, Accessed March 23, 2020
13. Malhotra, Girish: Are US FDA 483 Citations a "Medal of Honor" or “Rite of Passage” to Disgrace for the Pharma companies? Profitability through Simplicity, October 16, 2019