ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must.

Excellence is expected from every task we humans do. Definition of excellence differs between humans. Due to lack of product quality consistency and excellence in pharmaceutical produced products, US FDA was created in 1906 ⁽¹⁾. If we review the history of the US Food and Drug Administration its prime motive is to assure consistently excellent quality products (food, pharmaceuticals and cosmetics) that deliver the same performance all the time.  

Going fast forward, since I had not been involved in ANDA filings, I recently started to learn the task. I found it an extreme challenge. The process is cumbersome and even a priority approval takes time ⁽²⁾. I spent significant time to understand, determine and accumulate what all is needed to simplify a filing and create an ANDA application to have an approval in three months from the current expectation of ten months. FDA’s goal of approval in ten months from past practices would be a significant improvement ^{(3, 4)}.  

Being a chemical engineer, I am trained to follow and communicate using a process flow diagram for the process at hand. Block process flow diagrams ⁽⁵⁾ are one of the way chemical engineers communicate information about the processes to their colleagues. Such process flow diagrams have been in use since 1840 ⁽⁶⁾.

Hoping to find a similar diagram for ANDA filings, I searched FDA websites. Yes I did find many documents that tell the readers what all is needed but I could not find a single document (showing a process flow diagram) that would tell me or anyone precisely what are the documents and information needed and their sequence. [If anyone knows existence of such road map at FDA site, please let me know.] There are lots of guidelines and guidances but during discussion with fellow professionals, I found they have different interpretation of requirements.

Simply said these documents (guidances) suggest that if five different companies were filing an ANDA for the same drug it is quite possible that none of the submissions would be exactly the same. I wonder how FDA staff will do if asked to file ANDA for a generic drug. FDA site has links that link to different documents but there are no simple flow diagrams ⁽⁷⁾. One can get lost in the maze. I would not be surprised if the number of pages in these guidances could exceed an ANDA filing application.

Since I could not find a flow chart for ANDA approval process, I thought a flow chart for New Drug Approval (NDA) ⁽⁸⁾ might exist. To my chagrin I was disappointed. Again, there were links.

The US FDA has done an excellent job in documenting and guiding what paper work is needed but I am afraid that paperwork as stated earlier can lead to personal interpretation of what all is needed and it most likely is the main cause of variations and inadequacies in filed applications and leads to delays in ANDA and NDA approvals.  

Best way to simplify the process, my perspective, would be to create/draw a road map that details each marker at every step of the way and nothing is left for interpretation. Each desired parameter has to be defined and even illustrated if need be. Simplicity is needed.

Process of filing approval for the Brand and Generic drugs is similar to any manufacturing or a service process. Every filer desires to produce a quality product (aka QbD “quality by desire”) filing. However, the current filing process can be labeled a QbA product “quality by analysis = aggravation” as it is based on individual interpretation of guidances and guidelines. I believe as stated earlier is the cause of delays and resubmissions.

I hope that once the road map for ANDA/NDA filing is created someone at USFDA will follow the road map and a file an application. Such filings should then be reviewed internally and the roadmap/ flow diagram tweaked to assure perfection. Such a process will define discrepancies and simplify the filing process. There could exceptions but in general the process will assist everyone. If done, it will lower the effort and costs related to filings. Another latent but a magnificent benefit will be that the companies will create an excellent document that is based on filers desire to create excellence. It will be a QbD (design/desire/diligence) document based on a quality by design process. I am confident that it will also assist companies to create repeatable and excellent processes that will produce quality product.

Girish Malhotra, PE

President

EPCOT International

1. US FDA History Accessed May 10, 2017
   
   
2. Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Accessed May 10, 2017
   
   
3.  Generic Drug User Fee Act Reauthorization (GDUFA II) Accessed May 10, 2017
   
   
4. Testimony of Drs. Woodcock, Marks and Shuren Accessed May 10, 2017
   
   
5. Process Flow Diagrams Accessed May 10, 2017
   
   
6. Cotton Processing Flowchart, Accessed May 10, 2017
   
   
7. Abbreviated New Drug Application (ANDA): Generics Accessed May 10, 2017
   
   
8. New Drug Application Accessed May 10, 2017

Can Senate And House Bills S2615 And HR 4784 [Increasing Competition in Pharmaceuticals Act] Alter the Pharmaceutical Landscape?

Senate and House bills [S2615 ⁽¹⁾ And HR 4784 ⁽²⁾] are an interesting attempt by the US government to increase competition in the pharmaceutical industry. One would and if they have not asked the question, should ask why the pharmaceutical industry has to be coaxed or nudged to compete. Shouldn’t that be the natural part of the business process for the companies to compete, be the most profitable and have the largest market share?

A review of the two identical bills suggests that there are issues with the proposed bills. In my estimation, it is highly unlikely that the US government or for that matter any government would succeed in guaranteeing the necessary lower priced generic drug supply. Desire to compete on product quality, price and profits has to come from within the industry. Government has to lower the regulatory barrier while holding companies accountable for any missteps.

Two proposed bills are a half-hearted approach to generate enthusiasm in the industry but red tape and slow process will mire the path to reduce time to market.

Language of the proposed bill “The Secretary shall prioritize the review no later than 150 calendar days after the date of the submission of an application that has been submitted and accepted for review under this subsection, or on a supplement to such an application” suggests to me very clearly that regulators are the bottleneck and these bills do not solve the problems.

The proposed bill suggests intervention by the Secretary “no later than 150 calendar days”. This in itself suggests that is system is flawed. Applications should be sequentially prioritized as they are filed. If the regulators cannot get the review completed on a timely basis and get the product commercialized, we all need to look at the value of the proposed bill. Industry and regulators need to develop and promulgate a program that that assures quality and safe drugs at the lowest price on a timely basis.

I suggest the following modifications to the proposed Senate and House bills. Industry and the regulators have to on top of their game to deliver the best results.

Since company’s intent is to make profits, they should have every “t” crossed and “i” dotted about the process and method of manufacture before they submit review application to the regulators. Industry needs to wean itself from the regulators. Do this or that or this is missing or explain why is a clear dialog between the company and regulators is an indicator that the company does not and would not have command of the process and produce products by repeated analysis [quality by aggravation].

Company’s submission of the best of the technology, quality control processes, inventory management and business process information would be clear indicator that they can commercialize the product as fast as possible. Such an attempt will reduce the regulatory review process and time. That should create competition. If the submitted information is flawed or incomplete, the application under review should be returned to the company for completion and if the company decides to submit their ANDA application, the process time clock would start all over again. This would be an excellent indicator of company’s command and capabilities of commercializing a process that produces quality products. Repeated back and forth between companies and FDA would suggest there are serious issues at the companies.

US Legislature has recognized that there are delays in getting necessary approval from the USFDA. To expedite the process review the “review clock” should start from the day ANDA approval application is submitted. Regulators should be given maximum of 150 days from the date of filing to finish the review and act on the application. If the company has submitted all of the necessary information and their application can be approved in 150 days or less, they should be given “priority review voucher” which they can use for future submissions or sell to any other company. Issuance of priority review vouchers could be on a sliding scale. If the company’s ANDA application is approved in 90 days, Applicant Company gets two “priority review vouchers” and one “priority review voucher” if after 120 days.

My conjecture is that the proposed changes in the Senate and House bill would get the ANDA approved faster, increase competition and lower costs. A transparent ANDA application progress indicator that is updated on FDA website would be of great value. Some of the vested interests would intervene but my hope is that the best should come out that would benefit companies, patients and the pharmacy benefit managers. Current Senate and House bills are toothless and worthless as far as lowering drug prices and increasing competition.

Girish Malhotra, PE

President

EPCOT International

1. S.2615 - Increasing Competition in Pharmaceuticals Act, https://www.congress.gov/bill/114th-congress/senate-bill/2615
   
   
2. H.R.4784 - Lower Drug Costs through Competition Act, https://www.congress.gov/bill/114th-congress/house-bill/4784