Impact of Regulations, Drug Manufacturing and Pharma Supply Chain (PBMs and allies) in Drug Shortages and Affordability Part 1

Drug prices and shortages are becoming an ever-increasing issue. They need to be addressed. Regulations, Parma manufacturing and Benefit Managers and the supply chain have an impact. Since there is too much to cover, I am presenting my perspective in two parts. 

There are opportunities and they might be worth attention. Observations and views are mine and no reflection of any entity’s performance. Opportunities are there, waiting for us to be exploited and improve the landscape. There is no financial relationship with any company. 

Landscape and some “out of box” thoughts on how and what to improve are considered and reviewed. My perspective is on issues from “FDA to patient” which includes regulators, pharmaceutical manufacturers and distribution”. 

Part 1: 

Many have expressed their opinions. Legislators⁽¹⁾ and regulators ^{(2, 3, 4)} have organized meetings and discussions to figure out how shortages can be alleviated and drug prices contained to a reasonable degree. Pharmaceutical companies and PBMs (Pharmacy Benefit Managers) have stalled and intervened every attempt to control drug pricing that will upset their apple cart as they could lose a lot. Legislators want to intervene but due to political influence of the industry have shrugged away from the wants of their electorate. Suggestions have been made to ease drug shortages but nothing has worked except for talk.  

“Creative Destruction” ⁽⁵⁾, “Nondestructive Creation” ⁽⁶⁾ or coup d’état are potential improvement pathways. Persistent effort and planning would be needed. We must recognize that there will be significant internal resistance and powers to be will intervene and make sure “nothing to very little” is altered.

Not much will happen instantly. We must understand the existing landscape, reconfigure it and make the necessary changes. It seems process of “continuous improvement” has been overlooked from FDA to patient. Unless an effort is made we could be still talking about the change for the next 10 or 20 years. 

Drastic measures like single payer system, drug price controls and government edicts can control price increases and shortages. A President’s “National Healthcare Emergency” equivalent to “National Border Emergency” ⁽⁷⁾ is another alternate. There will be significant opposition against altering the current way of doing business. Intent here is not to take drastic steps but create wins that would lead to big wins for all involved. 

What all is possible?

Since there are many players (regulators, pharma companies, middlemen) involved, my conjecture is that selective application of “Nondestructive Creation” and “Creative Destruction” would be needed to achieve lower drug prices, reduce shortages, and retain profitability of everyone. Assistance of legislators would be helpful to smooth out the landscape. Even though each participant is independent but influences each other. If we can simplify/improve each, we will improve a lot. 

Existing processes can be simplified, innovated and competition instilled with two objectives: enhance profitability of pharma related companies and improved drug affordability with minimum or no shortages. If we put our heart and mind to improve the existing system it can be improved. As I said earlier there will be resistance as the easiest thing us humans love to say “NO” it won’t work. Unless we try, nothing will change. 

We all know that competition leads to manufacturing technology innovation, better and consistent product quality, better prices, minimum shortages, and improved profits of every participant in the business. It seems that in generic pharma manufacturing and distribution we have “organized lack of competition”. It could be due to influence of brand drugs and the sentiment “patient will pay the demanded price to extend their life. It is interesting to note that no one knows the real drug prices except what patients pay after copay. What patients pay is not realistic as they are mutually subsidized prices. We also need to look at the total landscape to see interferences and simplify them to tackle affordability, profitability, and price issues.  

Regulations (ANDA and NDA Approval Processes): 

In the United States FDA is responsible for assuring product quality and consistency. Companies are expected to get approval of every new (NDA), generic (ANDA) or OTC (over the counter) drug prior to their sales ⁽⁸⁾. For product consistency and quality, companies must follow FDA’s established cGMP guidelines. They are expected and do use established and appropriate economics and engineering principles and methods to produce drugs. Economic justification, like in any other business, is necessary for use of every process and technology.  

FDA has a guidance (process or road map) for ANDA/NDA approvals ⁽⁸⁾. I consider filing and approval process equivalent to a manufacturing operation. For these filings FDA must give precise road map of their expectations (I call them operating instructions) that any company (equivalent to a plant operator) should be able to follow and get approval (create a quality product) in three months. These operating instructions must be clear and broad enough to cover every ANDA/NDA filing and produce a quality product from the get go. 

My conjecture is that most likely FDA knows what is needed for approval but either the companies don’t completely understand the needs and wants or have become accustomed to FDA’s hand-holding to take them across the finish line. Based on my review, the current process is complex and needs significant legal and engineering manpower to file an application and get an approval. There is some discussion to lower the current approval times but it is not going to be significantly different ⁽⁹⁾.

In every manufacturing organization, process operating instructions are pilot tested. My expectation is that FDA similarly pilot tests their ANDA/NDA instructions internally before these instructions are issued (commercialized). If FDA’s operating instructions cannot be followed the first time, it suggests these instructions may not have been pilot tested. In FDA’s own terms if they do not fit quality by design (QbD) process but fit quality by analysis (QbA) (A could be aggravation) mode. Based on my experience, I have found that practicing/testing the operating instructions before commercialization is an excellent way to learn their shortcomings. This exercise is an excellent example of “nondestructive creation” can be used NDA/ANDA filings also. 

My speculation of “untested instructions” is confirmed by significant “back and forth” (long time) the current review process takes to get an approval. To me that means that the operating instructions are not precise and/or clear. The resulting product (ANDA application) is not a quality first time but a re-worked product. In manufacturing operations “re-work” means lower profits. In financial terms “ANDA approval after rework” is delay in commercialization and delayed profits to the applying company. I believe significant improvements can be made to simplify the existing process so that better than 95% of the hand-holding can be eliminated. Saved time would have higher profitability, lower cost and affordability implications, a big win for all.

Since the current filing and approval process takes time, question needs to be asked to the Regulators is “what can they do to simplify the path and approval to bring drugs to the market?” Again, this would be a great  profitability through simplicity opportunity.

Companies deciding to file for approval can take as much time as necessary to complete and file the application. Each filing company will submit their information in FDA’s requested format even though they produce different products. Again, I want to emphasize that these pilot tested operating instructions, if followed precisely, should produce a quality product which would result is an ANDA approval in three months. 

Recently introduced Competitive Generic Therapies Guidance draft ⁽¹⁰⁾ is supposed to give companies competitive advantage. Competition, to me, means be first in the market. I don’t believe companies will get any such advantage as the suggested process is cumbersome and battery of personnel (legal and otherwise) would be needed for submission. I also ask the question “has the guidance been pilot tested within FDA to see the challenges it poses for submission and approval and does it meet FDA’s own Quality by Design (QbD) expectations proposed in 2005?” It would be extremely useful if FDA, based on its internal pilot test, can simplify the process and suggest the time it would take from start to finish to file and get an approval. 

Regulations: ANDA Term: 

FDA’s existing evergreen ANDA approval regimen can be exploited and abused. US FDA should consider changing its evergreen policy. As explained later, if adopted, it may encourage competition. US being the largest and most profitable market, almost every company would like to sell their products in this market. However, their products must be on some formulary. If a company’s approved ANDA drug is not manufactured for sale in the US and is also not on any US formulary one-year after approval, ANDA should be revoked. In addition, if the approved ANDA is licensed out to and produced at an un-inspected FDA facility, ANDA should be voided. If a company later wants to sell their products in US, they would have to re-apply. This would prevent companies from using and overloading US approval system to promote their products in other countries. My conjecture is only companies with best technologies, cost and quality based on economies of scale should serve the US market. 

About 30% (~2491) of the ANDAs are with 90 companies ⁽¹¹⁾ and this basically suggests that likelihood of economies of scale, optimum processes, is minimal to none. Rest (~69%=5,475) are with ten companies ⁽¹⁰⁾ which are being manufactured in about 200+ plants. Again, my conjecture is that these products have no benefits of economies of scale most drugs are produced using mediocre manufacturing processes and are not the lowest cost producers. It is very likely that they, as explained later in Part 2, face many challenges. 

Since FDA must monitor each ANDA facility at a prescribed schedule, I am not sure FDA has sufficient staff. It is ironic that FDA does not know how many of the ANDAs are not being marketed ⁽¹¹⁾. If an annual report is not submitted within FDA’s guidelines and the granted facility inspected, related ANDA should be voided and could present opportunities to the companies that are producing the same product/s to other companies. All voided ANDAs should be publicly listed. Expiration and voiding of ANDAs might result in consolidation and competition for the market through economies of scale (better technologies) and costs, which is dearly needed. 

If PBMs are forcing companies to have certain number of ANDAs to be on the formulary but not marketing all, ANDAs not being marketed should also be voided. This is discussed in Part 2. 

In Part 2 of this blog I will share my perspective on Manufacturing and Pharmaceutical Supply Chain (PBMs), Drug Shortages and Affordability. 

Girish Malhotra, PE

EPCOT International 

1. Senate Finance Hearing on Drug Pricing, C-SPAN, February 26, 2019
2. Strategic Plan for Preventing and Mitigating Drug Shortages, FDA, October 2013, Accessed November 21, 2018
3. FDA is Advancing New Efforts to Address Drug Shortages, FDA, November 2018, Accessed November 19, 2018
4. The Duke-Margolis Center for Health Policy, Identifying the Root Causes of Drug Shortages and Finding Enduring Solutions, November 27, 2018
5. Schumpeter, Joseph:Capitalism, Socialism and Democracy, 1942, Accessed November 29, 2018
6. Kim, Chan W., Mauborgne: Nondisruptive Creation: Rethinking Innovation and Growth, MITSloan Review, February 21, 2019
7. National Emergency, The New York Times, February 15, 2019 
8. ANDA Submissions — Content and Format Guidance for Industry
9. Testimony of Drs. Woodcock, Marks and Shuren Accessed March 23, 2017
10. Draft Competitive Generic Therapies Guidance, FDA, February 2019 
11. Berndt, Ernest R., Conti, Rena M. and Murphy, Stephen J: The Generic User Fee Amendments: An Economic Perspective, NBER Working Paper 23642, August 2017

Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution

Most get excited about the drug shortages when they happen and start a discussion how they can be prevented. Problem has been thereandit is getting to worrisome levels. Shortages can also be used as a weapon against the US population. 

Regulators have proposed strategies ⁽¹⁾ to alleviate these shortages but they have not worked. Actually shortages are getting worse. Had the 2013 strategy ⁽¹⁾ been effective, the current discussion ⁽²⁾ would not be taking place. Each participant (manufacturer, supply chain participant and regulators) in drug supply chain has to participate and alleviate the problem. One of the difficulties of the current pharmaceutical system is lack of clarity and understanding of the drug distribution system ^(3,4,5). Current distribution system has been blamed for the shortages ⁽⁵⁾. Supply chain system has made every effort to make sure no one is able to penetrate their fortress and understand how things happen. 

I also believe that the current regulatory system may be latently aiding the current shortages and needs to be reviewed and simplified. Each participant has to participate to different degree to alleviate the problem. Many might not agree with this conjecture but if all was good we would not have the drug shortages. Fundamental change is needed in the pharma’s business model and it would be have to be disruptive. As discussed later there will be tremendous resistance to any change. 

I have my own over simplified description for three players on the drug landscape. 

1.     Drug producers: These companies discover therapies and commercialize the approved drugs using the best manufacturing technologies to maximize their profits. When drugs go off-patent, generics step in. 

2.     Supply chain intermediaries: Their mission is to facilitate drug distribution, manage healthcare programs and be extremely profitable. Reference ⁽⁴⁾ is worth the read as tries to explain the workings of PBMs and it is educational. I am sure they might be other descriptions of the process.  

3.     Regulators: Their mission is to assure safety of drugs and that involves companies follow strict regulatory guidelines.  

Problems of future drug shortages have their latent start when drugs are commercialized. We may not want to acknowledge this but have to recognize that each participant plays itspartin drug shortage at some point in the life of each drug. Some more than others. Common hypothesis is that the other party has created the problem and will address the issues. No one does and this keeps growing till it becomes acute. Every participant has to do its part thoughtfully to eliminate/reduce shortages.  

Solution for Drug Shortages:

Like in any business if the buyer keeps squeezing the seller on price, sooner than later if the seller cannot make their desired profit to stay in business, they will stop producing, and if shortages ensue, it is not their problem. This holds very true on pharma landscape ⁽⁵⁾ also. As explained later I believe that regulations are also part of the problem. 

Following is my overview of the landscape and potential solution. This will need to be fine tuned. 

Competition⁽⁶⁾ is healthy for every business. Pharma, especially the generics, need to have the environment to compete. They don’t have the desired environment. FDA’s current ANDA approval methods and practices come in the way of creating competition. It just takes too long and multiple iterations to get the application completed and approved. This process is expensive. FDA will have to play the role of creative destructionist ⁽⁷⁾ andchange its ANDA approval process to 90 days ⁽⁸⁾or less. With 90-day approval some of the generic producers could become proactive and may want to compete and supply to the market as soon as they see drug shortages. With shorter approval time companies would have the opportunity to use the best manufacturing technologies and stay profitable.

Breaking the current ^{(3, 4)} drug-delivery supply chain consortia is the key to eliminating shortages. Pharma’s current drug distribution business model (everything that lies between the manufacturer and the patient) has to be disrupted ⁽⁷⁾. Supply chain consortia has and will resist its breakup and politically do everything possible to scuttlebutt wholesaler - healthcare facility - drug seller linkage. It is a juggernaut ^(3,4) that needs to be cracked. However, with the current political influence of consortia on our elected legislators, it is going to be difficult to crack. For short term a Presidential Executive order might be the only answer. If that happens there will brouhaha of government intervention in free market economy. However, when patients die due to lack of drug availability, we need to ask ourselves a question “what is important profits or life?” Most will opt for life. 

Drug distribution consortia can be disrupted in other ways. Legislative support would be needed for the disruption. This consortium has and will use drug safety as an argument against anyone else who will encroach on their turf as they have done in the past e.g. patients trying to get drugs that are lower priced from Canada or elsewhere. It is fascinating that the members of the consortia tell the legislators (who are being funded by the pharma industry for their re-election) that the drugs from these countries will be not be of quality but turn around and buy from the same producers’ products to sell in the United States. 

Disruption of the supply chain consortia can be easily done if FDA allows direct import of the drugs on the shortage list by major hospitals (Cleveland Clinic, Mayo Clinic or other large buyers) and similar buying entities e.g. Veteran’s Administration, Amazon (PillPack) and bypass the supply chain consortium members. PBMs will do everything to stop anyone looking ⁽⁹⁾ at their inner sanctum by offering to participate in any alternate drug distribution as they supposedly have done for Amazon, Berkshire and JP Morgan alliance. 

Supply chain consortia, as stated above, in the name of facilitating drug distribution and drug safety, is also responsible for the current prices. Prices should be significantly lower ^{(10, 11)}. Additional examples of prices of randomly selected drugs are illustrated in Table 2 ⁽¹¹⁾ and Table 1 ⁽¹²⁾ of the linked. Actually if the generic manufacturers from the developing countries can be the direct supplier to the developing countries there is an opportunity not only to reduce/eliminate drug shortages but also to significantly lower the generic drug prices in the developed countries. 

Companies who can supply shortage drugs will have to be from FDA’s ANDA approved companies list. 90-day approval window will encourage and facilitate many producers to participate. PillPack, Amazon and others can distribute the needed drugs. 

I want to re-iterate that if the above suggested proposal or anything similar is considered, wholesalers, PBMs and everyone in the middle of the supply chain will resist and lobby against thinning of their “cash cow”. Lobbyists of every kind will make sure that their current landscape that they have nurtured for long is not disrupted. There is too much at stake for the consortia. 

If FDA can create a 90-day ANDA approval environment, it is very possible that manufacturers in the United States might re-start their mothballed or invest in new facilities that will have best of the technologies to supply the US market. Potential threat of drugs that could be used as a weapon could be everted. We may see resurgence of pharma manufacturing in the United States. Going forward we need to think this aspect seriously.  

Another major win, if the consortia can be disrupted, would be lower generic drug prices, possibly improved affordability, that will come from the companies considering and using the most innovative manufacturing technologies like continuous manufacturing for sterile and other products. Manufacturing technology innovation that has eluded pharmaceuticals will finally become a competitive tool, if the pharmaceutical industry is willing to partake. 

Companies in a competitive environment, a worldwide phenomenon, use the best and most innovate technologies to produce products. Quality will be built in rather tested in. FDA will not have to suggest companies how and what of quality product and manufacturing technologies. Regulators will not have to be the purveyors of technologies as they have been doing without much success. FDA has set the product quality standards companies have to meet. Pharma companies will justify their own investment and should be able to ramp up their production to meet spikes in demand. At times I see many trying to test FDA suggested technologies and I wonder why are they trying to appease the regulators when the investment in technology cannot be financially justified . As I said earlier companies need to decide what technologies suit their business model to stay profitable rather than regulators suggesting them what would help. 

FDA and other regulators will have to be most vigilant and more critical in their inspections and ensuing actions. Companies that do not adhere to cGMP practices and regulatory protocol will have to be shutdown. FDA will have to employ experienced personnel who are well versed in process development, design and are knowledgeable about different manufacturing technologies. Experienced personnel will spot deviations from cGMP practices as well data re-jigging.  

Combination of current relationships between manufactures, supply chain and the regulators an environment of drug shortages has been created. If we have any desire to change the current mold it will need to be broken. There is an opportunity to revamp the pharmaceutical landscape but as said earlier there will be resistance. If a pilot program to eliminate/reduce drug shortages through direct distribution can be started and assured, we will have two benefits: shortages will be reduced and competition will be a big win for the patients through lower prices. Success could also result in resurgence of pharma manufacturing in the United States and other developed countries. 

Girish Malhotra, PE

EPCOT International

1. Strategic Plan for Preventing and Mitigating Drug Shortages, FDA, October 2013, Accessed November 21, 2018
2. FDA is Advancing New Efforts to Address Drug Shortages, FDA, November 2018, Accessed November 19, 2018
3. Follow the Pill: Understanding the U. S. Commercial Pharmaceutical Supply Chain, The Kaiser Family Foundation, March 2005 Accessed November 25, 2018
4. Eickelberg, Henry C.: The Prescription Drug Supply Chain “Black Box” How it Works and Why You Should Care, American Health Policy Institute, 2015 November 26, 2018
5. Koons, Cynthia: Why We May Lose Generic Drugs, Bloomberg Businessweek, April 11, 2018
6. Gardner, Eric: Competition creates innovation: Creative Destruction & America’s problem, ericgardner.net August 10, 2016, Accessed November 18, 2018
7. Schumpeter, Joseph: Capitalism, Socialism and Democracy, 1942, Accessed November 29, 2018
8. Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicity, November 25, 2018
9. Triple Threat: Amazon, Berkshire, JPMorgan Rattle Health-Care Firms, The Wall Street Journal, January 30, 2018, Accessed January 31, 2018
10. Sood, N; Shih, T; Van Nuys, K; Goldman, D; The Flow of Money Through the Pharmaceutical Distribution System, June 6, 2017, Accessed March 1, 2018
11. Malhotra, Girish: Comparison of Drugs Prices: US vs. India; Their Manufacturing Costs & Opportunities to Improve Affordability, Profitability through Simplicity, January 18, 2018
12. Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability though Simplicity, March 8, 2018
13. Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing, Profitability through Simplicity, July 20, 2017

Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape

FDA’s New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) approval paths in their present form are complex cumbersome maze and from my perspective need lots of luck and flawless interpretation of FDA’s needs for a first pass perfect submission and acceptance. FDA has suggested that it is working on a plan to lower the review and approval time ⁽¹⁾for priority drugs. If FDA can reduce the time for priority drugs, it can also do the same for every other drug. Simplification is needed ^(2,3,4). Considerable effort on part of companies and FDA would also be needed. If accomplished, companies and patients could realize the following benefits. 

1.    Lower approval time will lower regulatory costs and improve affordability.

2.    With faster approval companies will be able to have additional revenues.

3.    Drugs would be available to the patients sooner than the current times.

Pressure has been and is being exerted by the general population on regulators ⁽¹⁾and legislators to reduce the approval time. For the drug safety regulators need to review the necessary information. 

Form 356H ⁽⁵⁾seems simple, but meeting every requirement one has to follow 21CFR314 ⁽⁶⁾and that is a challenge. From my perspective the current process ^(6,7)is cumbersome and complex. It seems to be fraught with what I call considerable legalese, extensive intellectual complexities and ambiguities. An average person will require lot of explanation, hand holding and simplification to complete the necessary requirements. 

I have my own perspective of how the ANDA approval process can be simplified and still meet what is required by FDA and other regulatory entities. My proposal most likely would be taken as oversimplified version but could be a starting point to revamp 21CFR 314 ^{(5, 6, 7)}. ANDA Submission ⁽⁷⁾has only 38 pages but due to included references is no different from its longer version⁽⁵⁾. 21CFR 314 ⁽⁵⁾should be reviewed and simplified every so often e.g. every five years or less to meet the changing needs of pharmaceutical landscape. It should be part of FDA’s internal “continuous improvement” process. It could be considered a living document creating a “quality by design (QbD)” product. If the suggested simplifications are pursued and ultimately adopted, the NDA/ANDA approval would be much simpler than what we have and companies would realize the above suggested benefits. 

Information submitted and the filing process might not be any different from what it is today but would be much simpler step by step process as it can be easily understood by any one who is completing the application. No special expertise might be required. 

Today’s process as stated earlier requires considerable knowledge of the maze and how to comply. Many current “what if’s, dos and don’ts” of the legal maze need to be simplified and eliminated. It is my conjecture that information needed by FDA will give companies a clear definition and total command of everything one needs to know about the drug. With 90 day or less approval time companies would have incentive to do a quality filing. In FDA’s vocabulary I would call such filings “a QbD filing”. Today’s NDA/ANDA filings are a “Quality by Analysis (aggravation) QbA” filing. This needs to change.   

In Table 1 I have attempted a simple skeletal outline which could be used by the regulators to create an extremely clear and concise road map that could be precisely followed by a company for a complete application from the start. Filing requirements for NDA and ANDA fillings process would be simplified if each had their own their road maps. Elements of the road map from regulators would clearly define what they need and the industry needs to submit for a complete submission from the start. FDA or other regulators would review the submitted information for completeness and make necessary decisions to have the submitted filing granted in 90 days or less.  

I would not be surprised that many who are associated with regulatory filings and their processes would say “filing simplification can’t be done”. Effort would be needed. Change is inevitable and a necessary reality. We have that capability especially when we can send a human to the moon and brought him back safely.   

In my efforts to figure out how simplification can be done I reviewed perspective of others ^{(9, 10)}. These are interesting and should be reviewed by FDA to create the best and the simplest process. I am sure there are other ways also. Each perspective illustrates some of the challenges. They take us through the maze and could be used for simplification. Page 15 of reference 9 has a simple flow chart (road map) that could be used as a simplified process diagram for ANDA and NDA approval. FDA personnel should be familiar with Ishikawa and other logic diagrams. Such diagrams could be used to create new or be updated to improve filing and approval process. Reference 10 articulates the path via a written document.  

Again, FDA has to clearly spell out in details what information is necessary and needed from a company so that its ANDA/NDA application can be approved in 90 days or less. Spelling out the needed information and its simplification is FDA’s job as it is the most knowledgeable authority to define what is needed for approval. Based on my reading parts of CFR314 there are just too many “what ifs, dos and don’ts.” Understanding the maze can be a challenge. An Ishikawa Diagram ⁽⁸⁾or a similar logic diagram would be of great help. 

Company can take whatever time they needed for the initial submission. Once the company submits its application and FDA receives the submitted application that day becomes DAY ONE. 

In my ANDA/NDA review and approval path design each submission from the filing date gets two paths at FDA and they run parallel as illustrated in Table 1 and it looks very simple in its format and it is.

ANDA/NDA Approval Application
Inspection Path:	Application Review Path:
Based on the submitted application it is assumed that it is complete and no additional information is needed. FDA sets up the mechanism for an inspection date for the applicant site. Time period for the inspection has to be between Day 45-60 from the date of submission. These dates could be changed or cancelled based on FDA’s Application Review Path. It is important to make companies aware of the timetable so they are prepared for the inspection. This should be spelled out in the FDA road map.  If FDA informs the company of its completed application, company has to make every arrangement for such the inspection. If company does not agree to such inspection in the time window, future NDA and ANDA applications of the company should not be accepted for a prescribed time e.g. ONE year. This stipulation assures that the companies filing for approval are legitimate companies.	FDA starts the application review. If FDA does not see any discrepancy or the missing information within the first thirty days, submitted application should be deemed complete. FDA informs the company and the inspection date details that started date ONE is firmed up.  If any of the submitted application is deficient or has missing information or an explanation/clarification is needed, FDA informs the company within the thirty days or sooner from the Day One date.  FDA has to detail what all it needs for a complete application. Company has to submit the information to FDA for completeness in the next thirty days to retain its inspection date between 60-75 days from the original submission date.  If the company cannot complete and submit the needed correction/s, application goes back in the queue and the 90 day process with no fee starts all over again.  More than one FDA rejection should be deemed as a failure and no submission for the same drug should be accepted for the next two years from this company. If the company does file for the same drug it will have to pay necessary fees again. If FDA does not send any company any feedback in the first 30 days, the submission would be considered complete. If FDA does not approve the submission after 90 days, it will have to explain in writing its reasons. If FDA does not respond in any form, the submission would be considered approved and not subject to any reexamination for some time e.g. one year. However, this does not relieve company of meeting FDA's quality standards.

                                                                        Table 1

Two parallel paths should lead to a process that will be fast and could result in 90 day or less time approval.  Again if FDA chooses Ishikawa or similar process paths my conjecture is that Form 356 and CFR314 will become clearer and simplified. Resulting impact on the pharma landscape would be beyond our imagination. 

One of the most challenging tasks for filings these documents is understanding and overcoming mountain of acronyms and clauses one has to deal with in submitting the necessary and needed information. Understanding the alphabet soup is daunting. Simplifying them would be a challenge and could be resisted by some as it could impact their business. 

Again, FDA has to start, lead and complete the simplification process as they know what all is needed for a safe product. FDA could test simplification hypothesis internally using one selected group to compile and fill the needed information simulating submission and other selected group to review and critique the submitted information for completeness and approval. It would be a simulation of the filing and a review process. How much time the two processes take would be an excellent gauge of what all is needed to create a 90-day approval process. As stated earlier filing group can take whatever time they need but the reviewing group will have to complete the approval/disapproval task in ninety days. 

I would not be surprised if FDA has already done such simulation but most likely have not publicly shared the results of the exercise. If they have not done it, that suggests that they most likely did not have a 90-day approval process in mind. Maybe it is time.  

Reference 9, is an FDA presentation, has very interesting information about the number of approved, backlog and received ANDAs. These numbers raise a question and it is “Are the global companies filing ANDAs for the same drug and using FDA approvals to market their products in countries other than the United States and overburdening developed country regulatory system?” If so, such practice has to be stopped. Another question with so many filings is “Are the US PBM’s (pharmacy benefit managers) using FDA’s approval system to weed out companies to their advantage and maximize their profits, by artificially creating competition and dumping companies that do not meet their profit criterion”. 

If the above 90-day road map can be promulgated and adopted my conjecture is that the pharma landscape will change. This is discussed in an upcoming post. 

In any manufacturing or service process of continuous simplification is a must. It should be mandatory even for every regulatory ANDA/NDA filing and approval process. Opportunities exist. Improvements will lower prices and should improve new and generic drug availability and affordability. Better affordability should also improve revenues. It would be an overall win for humanity and there is nothing wrong with that. 

Girish Malhotra, PE

EPCOT International

       1.  Testimony of Drs. Woodcock, Marks and Shuren

2.    Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity

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

4.    What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity

5.  APPLICATION TO MARKET A NEW OR ABBREVIATED NEW DRUG OR BIOLOGIC FOR HUMAN USE, Form 356H

6.    21CFR Part 314 Applications for FDA Approval to Market a New Drug, FDA

7.    ANDA Submissions – Content and Format

8.    Ishikawa Diagram

9.    Ya, Dr. Naiqi, Deputy Director, Division of Chemistry IV Office of Generic Drugs, Generic Drugs – Application and Regulatory Review, Accessed November 14, 2018 

10. Sullivan, Thomas: FDA ANDA Submissions Content and Format of Abbreviated New Drug Applications, Policy & Medicine, May 6, 2018 accessed November 10, 2018