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

What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days?

Approving pharmaceutical manufacturing NDA/ANDA [New Drug Application/Abbreviated New Drug Application] applications at FDA in three months could be considered a Herculean task for the application filer (company) and the regulators (FDA) and it would be. But, what if, it could be done. If achievable, we would see significant changes on the pharmaceutical landscape ⁽¹⁾. Monies would be saved in dealing with regulatory affairs, would reduce the time to market. That would mean higher revenues and profits for the brand and the generic companies. It could also lead to increased competition and potentially improve drug affordability though lower costs. There would be challenges to create and incorporate such a modified filing and approval process but the benefits achieved should outweigh them.  

The existing process of NDA/ANDA filing and approval is cumbersome and a challenge for the regulated and the regulators. I have not been involved but just reviewing the documents, what is expected and needs to be done, the process is cumbersome. I have to admit that I got lost in acronyms (alphabet soup), numbers e.g. xxx (w) (a) etc. and the legal jargon. No disrespect for the creators of the jargon, this alphabet soup gave me indigestion. 

I am sure there is process to accomplish approval in ninety days. For it to happen a precise roadmap ⁽²⁾has to be created and it has to be so good that it can be followed even with eyes closed.  

Expectations from the Road Map and What would be Expected from the Regulators and the Regulated:

Putting my process development, manufacturing and management hats simultaneously I am proposing a process that would have to be developed by the regulators (FDA) and the companies for their NDA/ANDA approval. I consider filing an NDA/ANDA filing equivalent to a manufacturing process that has to be followed precisely by both sides to create a quality product ⁽³⁾, an approved NDA/ANDA filing. 

Regulators based on their years of experience will write down precise step by step recipe that has to be followed by the NDA/ANDA filing company to get their approval in the slated time. I need to emphasize that if the regulators (FDA) precisely define their expectations, the process will be smooth. There will be no doubts about the expectations in the mind of the filers. Again, information asked has to be precise and cover every detail of type of manufacturing, synthesis as well as formulation, process. It is not going to be easy and can only come from chemists, chemical engineers and other engineering disciplines who have developed, designed, commercialized and reviewed such processes and products from head to toe day in and day out.

Yes, the companies might take their own time to file, their own choice, but the expected information has to be such that there is no finger pointing suggesting “we did not know what was expected”. If companies fulfill and deliver the information as expected and every deliverable is there, company should get their approval/disapproval decision in ninety days or less. That would be a huge win for all involved. There could be some back and forth but it would be minimal and the ninety-day clock, from the day the filing was submitted, will keep ticking. i.e. no stoppage. 

I would call regulator’s road map a quality by design recipe for a perfect process created by the regulators that the filing company will follow. If for some reason the regulator’s (FDA) recipe, the defined road map, cannot be followed or understood by the company, the application process will go from Quality by Design (QbD) to Quality by Analysis, aggravation, (QbA) and that means delays and added costs.  

Once the regulators have defined their needs to approve a filing, chemists and chemical engineers at the companies have to understand the questions and deliver the answers through their submissions. Both entities will have to understand each other’s paper conversation about every process. Only their dialog will produce repeatable quality product through the asked questions and the delivered answers. If this happens, the review process will go smoothly and time reduction mission will be accomplished. 

Companies submitting information will have to have an absolute command and knowledge of their processes and will have to present information so that it will convince the regulatory examiner/s that the product is going to follow every claimed expectation and regulation that has been laid out. In short product will be of consistent and repeatable quality. If this happens I envision that the approval process in the long run will be simpler and quicker than the current process.

Examiners at the regulatory bodies will have to understand the conversed information. In some instances clarification and or additional information might be needed. My expectation is that with time such cases might be few and far in between and the expended time would be significantly less than the present process. 

What would the Showstoppers say or think? 

There will be many who will be apprehensive of the suggested process. Their perspective would be mis-information could be submitted to get fast approval. Yes that is possible but the regulators have a recourse of barring or shutting down such rouge operations. That privilege will have to be used if the current legal system stands in the way. 

I am conjecturing that for the success of this proposal regulators will draw a precise map of what they need to have from the filers. It is going to easier said than done. Regulatory staff will have to be envision and document from their past experiences what all they need for a first-time complete submission. We have to recognize that it can be done but no one is going to welcome a voluminous dissertation. 

Let’s assume that every possible information FDA or any other regulatory body asks/needs for the approval is submitted to the utmost correctness the first time and the regulator have no questions. Would the regulators accept such an application without any apprehension and approve the filing in the 90 days or sooner from the first day of filing? I am sure that there will be doubters on both sides. It will take time to accept this process as it is outside the comfort zone of filers and the regulators.  

We have to accept that will not have a perfect road map from the get go. To get to the perfect stage, I am envisioning there will be lot of obstacles from the legal and consulting firms and even the manufacturing companies. Pilot program might have to be developed by the regulators and tested and over tested. Naysayers and doubters will have their days. However, if successful pharma’s landscape will change. I believe the best minds can create a process that is much simpler than what is being followed. 

I don’t have every “t” crossed and “i” dotted for the proposed process. I may sound repeating myself at times.  Objective here is to use the proposed process to build a system that will expedite the approval process. As stated earlier results will be higher revenue for the brand and the generic companies through speedier introduction of new therapies and out of patent generics, additional competition, possibly lower drug prices and inclusion of better technologies after the products are commercial. Process of continuous improvement would be included more than ever. 

We have an opportunity to play outside the box. It could be a hip-hip hurray moment. 

Girish Malhotra. PE

EPCOT International

1.     Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity, March 25, 2017

2.     Malhotra, Girish:ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must. Profitability through Simplicity, May 11, 2017

3.     Juran, Joseph M., Juran on Quality by Design, Simon and Schuster, ISBN 9780029166833, May 1992