How Would US FDA Behave/React if They Were on the Receiving End?

Corona virus COVID-19 has given us all time to think and conjure up things that can upset the established apple cart or improve it. We need and that includes FDA to simplify FDA’s approval processes and method if we want the drug industry to come back to the United States and be able to supply needed essential medicines. We have an opportunity. There is no financial affiliation with any for profit and nonprofit entity. 

The current global epidemic is not the last one. We could have many. We need to be self-sufficient to access the needed drugs. Why I say this? In the current and any future epidemic countries will fend for their needs. Case in point is chloroquine. Many have speculated that chloroquine can help in treatment of COVID-19. It is in short supply in US. US FDA asked ⁽¹⁾ Ipca Lab, India, to supply the drug for the US market when in 2017 Ipca Labs⁽²⁾ was banned to exports to US. Interestingly Indian Government banned chloroquine exports ⁽³⁾. 

If we want pharma manufacturing to come back to US, the FDA current review and approval methods and processes ^{(4, 5)} need to streamlined and simplified. I am sure US has a list of essential drugs. Stockpiles might not help if we cannot manufacture the active ingredients and formulate them in US.  

Should the US population revolt to bring pharma manufacturing home? Besides lip talk our legislator and the regulators would not do anything. In addition to bringing pharma manufacturing home, they have to compete against the best manufacturing technologies outside to produce quality drugs at the lowest cost. Many stars will have to align. 

In my recent post ⁽⁵⁾ I have tried to describe the current approval and application process. I am not a master of the application process, but if the pieces and parts of what I understand are true, we have an opportunity to improve. This will give the industry an incentive to come to US. I call my perspective “nondestructive creation” or an outlier thinking. Some or many could consider all this a farfetched dream and can’t be done. Well most thought man could not go the moon and come back. Well, we did that and some.

US FDA, like any manufacturing organization, where continuous improvement is routine, has to improve and simplify its NDA/ANDA review and approval processes. FDA has to shed its lenient methods (483 citations which I call “medal of honor” and take a tougher stand ^(6,7). Best of the best in pharma have to compete for the largest market. It’s not just the new drugs. FDA has to hold their feet to the fire. In addition, we need to be able to manufacture lifesaving drugs in case we need them for the next pandemic. We are not ready today as we can’t get chloroquine as explained earlier.

Every manufacturer practices QbD from the get go for every product. Industry practices “continuous improvement” in everything they it does. If they did not their products would have a very short shelf life. FDA has been preaching “quality by design (QbD)⁽⁸⁾”. Has it been practicing them for its NDA/ANDA review and approval processes? In addition, what has FDA done with respect to incorporate “continuous improvement” in its review and approval processes. My conjecture is and many others would concur that FDA’s current NDA/ANDA processes are quality by analysis/aggravation processes and could use improvements. 

May be their understanding of QbD is different from what they have been preaching. If regulators believe their current ANDA/NDA application/review/approval process pathway is QbD based then we need to reexamine QbD definition. My conjecture is FDA would not be pleased to see their QbD rating if there was such a scale. As discussed earlier ⁽⁵⁾ no one really knows how much time it takes to get approvals. With that said, I wonder how many companies would want to establish manufacturing plants in the United States. 

We need to be proactive and not reactive in bringing manufacturing home. In that effort we can also improve regulatory practices. If we don’t do it, another epidemic might not be kind to the US population. 

Girish Malhotra, PE

President

EPCOT International

1.     FDA frees India’s Ipca Lab from import ban so it can ship unproven Chloroquine for COVID-19 treatments, FiercePharma, March 23, 2020

2.     FDA bans imports of Ipca Lab drugs, FiercePhama, June 19, 2017 

3.     India bans export of malaria drug Trump touted as coronavirus treatment, Fortune, March 25, 2020

4.     Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020

5.     Malhotra, Girish: GDFUA II ANDA (Abbreviated New Drug Application) Review Target of 8-10 Months should be a Cause of Concern, Profitability through Simplicity, March 24, 2020 

6.     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

7.     Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019

8.     Quality by Design for ANDAs, FDA.gov, Accessed March 26, 2020

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

Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America

US FDA recently finalized “Guidance for Industry on Applications for Drugs with Inadequate Generic Competition” ⁽¹⁾. and it tells us it is the same play with different buntings. This guidance/process is totally inadequate as it is mired in FDA’s current lethargic and controlling practices. It renames the existing ANDA approval process and suggests it will create competition. However, except for minor tweaks and window dressing it is no different from what has been and is the practice.

FDA has a unique opportunity to create a legacy, bring manufacturing jobs home and address national security issue dues to potential drug shortages. It can also at the same time let the companies innovate manufacturing technologies, lower manufacturing costs, improve profits and improve affordability. Unless a process of “nondestructive creation” outlined below is adopted and implemented, the new proposal is a useless exercise of no value. In the outlined proposal there will be challenges but compared to sending man to the moon, the process would be a cake walk. There is no financial relationship with any entity. 

Following proposal/road map will not only create generic competition but also assure continued strategic drug supplies to the residents of United States. Under this scenario FDA has to grant or deny ANDA applications in 90 DAYS from the date of filing if they are properly filled and submitted ^(2,3). For this to come to fruition FDA has to create ANDA a simple filing process and environment. FDA would use the current fee structures for ANDA application filings and approvals. 

For 90 day approvals to happen FDA has to tell the industry the exact information it needs so that the ANDA can be granted or denied in the allocated time. Application will be equivalent “process operating instructions” given to any applicant filing ANDA and if followed as designed, will result perfect application (quality product) that will be approved 90 days or less. With any filing applicant guarantees that is will produce quality products.

Such filing process will be equivalent to FDA writing operating instructions that any operator (company) can follow to create a perfect product (ANDA application). I equate this exercise to be QUALITY BY DESIGN operating instructions. If any applicant company decides to produce the API or formulate in the United States 

US Government should give companies preferential ANDA approval time of 30 days vs. the proposed 90 days which includes inspection if they manufacture drugs in the United States. US has used such preferential treatments in the past ⁽⁴⁾.  

Regulators and companies cannot have any meetings prior to filings to address/answer any questions. Once the application is filed no new additional information except for minor clarifications can be asked by the regulators. 

Companies participating in this process have make sure that they will produce the quality product that has been approved by US FDA and follow FDA cGMP requirements on continued basis. If on random testing or inspection their products in US market does not meet quality specifications which they had committed to in their granted application, NO 483s will be issued and their production shut down for the next TWO years.

FDA’s filing instructions (operating instructions) that would be detailed but general enough to apply to every API and formulations application ^(5,6) . It will necessitate that FDA personnel preparing such instructions have complete understanding of API and formulation processes. Once such instructions are prepared they will have to be internally tested by FDA reviewers to make the application perfect.  This would be equivalent to operators at a manufacturing site testing the operations instructions to see if they are able to produce expected quality product. If not, the processes would need to be repeated till they produce perfect quality product.

Following time table would be followed for ANDA submissions and their grant/denial. 

Plant in USA		Plant outside USA
Day 1	Application arrives at FDA	Day 1	Application arrives at FDA
Day 7 from the filing date	FDA informs the applicant company for completeness or asks for missing information or clarifications. If no additional information is needed the review process continues.	Day 15 from the filing date	FDA informs the applicant company for completeness or asks for missing information or clarifications. If no additional information is needed the review process continues.
Day 15 from the filing date	Company submits the needed information. Review process continues. Plant inspection is scheduled.	Day 45 from the filing date	Company submits the information. Review process continues. Plant inspection is scheduled.
Day 30	Company is granted or denied the ANDA application	Day 90	Company is granted or denied the ANDA application

Girish Malhotra, PE

President

EPCOT International

1.     Competitive Generic Therapies Guidance for Industry , March 14, 2020 

2.     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 Accessed March 15, 2020

3.     Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity,October 24, 2018 Accessed March 15, 2020

4.     Coronavirus shows US needs to restore pharmaceutical production — in Puerto Rico, New York Post, March 7, 2020 Accessed March 16, 2020 

5.     Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days?, Profitability through Simplicity, October 24, 2018

6.     Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019