Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2:

Part 2 is an overview of impact of manufacturing, causes of shortages and PBM’s role in drug prices and shortages. In Part 1 ⁽¹⁾ of the blog I have suggested that there are opportunities if regulators facilitate the processes. In this part, I am enumerating opportunities that are worth considering and can be exploited. Observations and views are mine and no reflection of any entity or their performance. There is no financial relationship with any company.

Manufacturing and Technologies:

All involved in pharmaceuticals understand the current landscape but still it is good to refresh. Pharmaceutical manufacturing has two distinct components: API manufacturing and their formulations (FDF: finished drug forms). At times I have seen in press, academia and even the regulators calling just the formulation to be pharmaceutical manufacturing. Without an API, there is no pharmaceutical/drug and the product is just a placebo of no value. Two make the whole. 

Manufacturing Landscape:

Table 1⁽²⁾ is a snapshot of the pharma’s current manufacturing landscape for some APIs and their formulations. It is worth understanding it. Since many sites are producing the same actives and formulating them, my conjecture is that most processes are fitted in the existing equipment ^{(3, 4)}, a feature of batch processing. This generally results in the processes not being the most economic compared to equipment designed for a specific product. Companies are also not able to take advantage of economies of scale. 

Since patients need pharmaceuticals to extend life they will pay the highest price. Pharmaceutical industry capitalizes on this sentiment in profit making rather than competition. No one wants to acknowledge this but the fact remains. Simply said, inefficiency sells in pharma, my perspective. Reverse calculations tell us how a drug is priced ^{(5, 6)}and one can see profits at different levels. This further explained later. 

Drug	Number of API Sites	Number of FDF Sites
Ciprofloxacin	22	536
Atorvastatin Calcium	44	865
Omeprazole	87	768
Modafinil	29	70
Metformin HCl	77	752
Metoprolol	41	338

Table 1

High concentration of ANDA’s with limited companies ⁽⁷⁾ also adds to the current manufacturing complexity.Since the same equipment is used for multiple products, any investment that will lower costs and improve profitability through process improvements or equipment enhancement for selected processes are difficult to justify. In addition, use of same equipment to produce different actives and formulate them necessitates stricter compliance with cGMP requirements. Asset utilization is not the best. As explained later, combination of all can be a leading cause of shortages and data integrity.Landscape is ripe for simplification and much higher profitability.

A methodical review of APIs and their formulations tells us that opportunities exist to improve profits and reduce shortages. “Nondisruptive creation” ⁽⁸⁾ and “creative destruction” ⁽⁹⁾ are two potential ways to make drugs affordable, reduce shortages and for the companies to make significantly more monies than the current levels. However, this requires out of the box thinking and a different business model. Both would be considered disruption to the current business model. In each case plants will use optimum and competitive manufacturing technologies. Such plants will be able to react to shortages quickly, make drugs affordable and satisfy the growing pharmaceutical needs of 80% of the global population ⁽¹⁰⁾. 

In “nondisruptive creation” ⁽⁸⁾ and “creative destruction” ⁽⁹⁾ models, number of plants producing APIs and formulating them will be considerably reduced through consolidation. Plants will be based on economies of scale, most economic processes, and can react to any market changes. As explained in Part 1 of this post, FDA’s quick approval path might encourage companies to compete using either of these models. In either of the models, companies can select APIs and their formulations that interest them and commercialize the best manufacturing technologies to fulfill global demand ⁽¹⁰⁾. 

Modafinil, Ciprofloxacin, Atorvastatin and Omeprazole, Metoprolol ^{(11, 12, 13, 14, 15)} are just few APIs that can be produced in their dedicated single plants using continuous process to meet the global API demands. Metformin and omeprazole most likely would need multiple continuous plants. API processes will be most economic and highly profitable. Multiple FDF facilities would be also needed for these products. Technologies for continuous API and FDF plants have existed for over 60+ years. 

In Table 2, number of sites from Table 1 are used as an illustration for Omeprazole. API volume is an assumption. Most likely each plant does not have the most economic process. If omeprazole demand is quadrupled, it definitely becomes a continuous process candidate. Batch finished dose plants still would be uneconomic. Since the current processes meet each company’s profitability goals, economic processes are generally not the consideration. 

API, Kg. /yr.	# of patients	# of 20 mg. tablets per yr.	Tablets/ FDF plant	API, Kg./plant
1,400,000	191,780,822	70,000,000,000	91,145,833	16,092

Table 2

Omeprazole and esomeprazole can be manufactured at a single properly designed continuous plant. FDF doses can be finished in less than 20 properly designed continuous plants. Manufacturing cost of drugs could drop as much as 40%. It is an opportunity. Fundamentals of engineering, science and economics will guide to the most optimum model and process. Companies will have to make sure that they do not succumb to regulatory, academic or equipment vendor pressures in selection of their processes. 

Since companies will have to file and get regulatory approval, my conjecture is that the likelihood of moving from the current model to the alternate models ^{(8, 9)} for the existing drugs are very slim. This is difficult due to FDA current approval process and companies would need to think out of the box, not an easy thing when they are profitable. 

For the landscape to change FDA and other regulators, as stated in Part 1 of the blog, will have to facilitate and create competitive environment for the companies. My hope is given an opportunity companies will do that ⁽¹⁶⁾.Going forward companies will have to decide their best options. Significant upside of consolidation will be a much smaller but extremely robust portfolio of the companies. They will meet any and every demand upturn or downturn with much higher profits. Methodology can be used for any drug.

Continuous Improvement:

Continuous improvement, a mini version of “nondestructive creation” can also be used to reduce shortages and improve profitability and affordability. Such programs are necessary. However, as stated earlier due to regulatory obligations, such programs can be a challenge. 

Every process improvement in API and Formulation has to be tested on commercial scale to make sure product quality has not changed. It is well accepted that improvements tested in the lab and/or pilot plant will have to be confirmed on commercial equipment. Process improvement for each product at each site has to be justified. Testing of improvements is necessary as companies have an obligatory duty to meet regulatory requirements. Testing on commercial scale takes time, effort and money and can interfere with regular production schedule. Just for these reasons they, at times, are procrastinated and/or avoided. 

Shortages:

In the business world, it is well known that shortages can result from any one or combination of the following. 

1. Lack of profitability for the product
2. Raw materials 
3. Product and production planning
4. Process equipment availability, breakdown/malfunction or poor preventive maintenance

If companies are forced to lower their profits from their desired levels and cannot justify improvements, it is very possible that they may not produce selected products and this can result in shortages. Companies with a large ANDA portfolio ⁽⁷⁾most likely will shy away from equipment modifications as they may lose their operating flexibility, unless they adopt an alternate model. Another factor that has measurable impact and cannot be overlooked is savings vs. investment. If equipment has to be added or modified for a single product and interferes with other products, it is very likely that the modifications cannot be justified or will be procrastinated and eventually can be the cause of shortages. 

 

Last three of the above are related to company’s manufacturing and management practices. 

Shortages due to the second and third items above can happen only if the manufacturing company is not on top of its game in anticipating market needs and production planning. Even seasoned players can overlook the needs or a surprise is popped by raw material suppliers or customers. Effective communication with suppliers can be ward off supply surprises. However, customer surprise can be anyone’s calling and an opportunity. Company’s desire not to produce the product due to its profitability below a certain level is its own choice. 

Manufacturing is affected by equipment availability, production scheduling, technology and equipment related issues. Companies must know their equipment and their capabilities. Missteps lower equipment utilization and can also result in shortages. As stated earlier “nondestructive creation” ⁽⁸⁾can reduce shortages. If manufacturing is on top of its game, demand ups and downs can be absorbed. 

Equipment availability/utilization, capabilities and that includes production schedule and preventive maintenance needs must be continuously reviewed. cGMP needs can influence equipment availability and scheduling complexity. If a company must repeatedly contend with same issues, it needs to review its operations, that includes staffing, equipment and process design. My conjecture is that ten companies producing ~69% ⁽⁶⁾of ANDAs must make sure no balls are dropped. I am sure that could happen even in optimally designed plants. My conjecture is that just to ward off such mis-steps pharma has excess capacity. 

Excess production capacity also tells us that most of the processes are inefficient along with poor asset utilization and there are opportunities to improve profits. However, compared to other industries pharma companies do not avail the opportunity as they are able to make good profits and don’t need to optimize their production. As stated earlier, even with overcapacity careful production planning is critical. We have to recognize that inelasticity of batch operations and cGMP practices at times prevent ability to cope up with sudden demand changes. 

Since batch operations operate periodically in a year, manpower and appropriate equipment availability can also throw production planning off schedule and can result in product shortages. Production volume and run length have significant influence. Longer production runs can be used to alleviate shortages, as practiced in other industries. In the manufacturing world, products with comparatively lower profitability and production volume generally get the least scheduling priority and can also fall off the schedule resulting in shortages. cGMP needs can push more drugs in this domain. As emphasized earlier process improvements even to reduce shortages must be approved by the regulators, companies hesitate to change and ignore shortages. 

My expectation is that raw material suppliers are also looking at the items discussed above as they must manufacture products for their customers. They would like to streamline their operations and improve their profits by bringing certainty. If their customers are supplying to the largest market, the US, I believe each will pay more attention to the needs of customers on the US ANDA list. These are assumptions that will have to be proven. 

Shortages can be reduced if companies have a good marriage of their products, technology and equipment. Companies have to be a “nondestructive creator” for their selected APIs and formulations. They need to re-evaluate their portfolio. Generally, batch product companies don’t look at the crystal ball but it needs to be looked at. My conjecture is that companies have all of the pieces parts that need to be assembled differently. Effort can be very effective in reducing shortages and improving profits. 

PBMs (Pharmacy Benefit Managers) and Insurance Companies: 

Growing up I was always warned “be careful of the middleman”. In the United States Pharmacy Benefit Managers (PBMs) are the middlemen between manufacturers and patients. They are the BLACK BOX. No one really knows the workings of this box but attempts are made ⁽¹⁸⁾. Insurance companies are also part of this BLACK BOX. Insurers love to take money but hesitate the payback. This is well known. 

It is fascinating that no one knows real prices in the US. They can be reverse calculated by anyone who is knowledgeable in chemistry, manufacturing and costing. Reverse calculations ^{(5, 6)} give us significant clues. Table 3 is an illustration of prices of some drugs that would be ex-factory after their margins. Second last column is tablet selling prices to PBMs that include every margin, FDF conversion cost, profits at every level. Ten times the API selling price should cover more than any cost oversights at pharma factory level. Last column are the selling prices in US with or without health coverage. It is easy to understand the price differentials and would make even the most naïve cringe. Selling prices for some drugs in India are documented ⁽⁶⁾. 

Drug	API $/kg	Mg./ tablet	Tablets /kg	API $/tablet	$ per Tablet 10 X API	Price per tablet in US, $
						With health coverage	With no coverage
Ciprofloxacin	24	500	2,000	0.012	0.12	0.20	3.58
Atorvastatin Calcium	302	10	100,000	0.00302	0.0302	0.02	3.50
Omeprazole	2	20	5,000	0.00004	0.0004	0.05	0.30
Metformin HCl	4	500	2,000	0.002	0.02	0.07	0.70

Table 3

Occupants of the supply chain black box have made sure it is not disturbed. Generally, such situations are an indication that there is a whole lot hiding which not many should understand. Listening to Drug CEO testimony ⁽¹⁷⁾, an interesting comment was made how drug prices are set. Higher list price results in higher rebates for the PBMs etal. companies and is the driver to be on the formulary listing. No one really knows the truth as there are many vested interests. Fact remains that the drugs are priced on the sentiment “patient will pay the highest price to extend life”. 

With ever increasing and higher drug prices fingers get pointed and the poor patient, who is trying to figure out how to buy medicines either mortgages her/is assets or at times must decide between their food and drugs dies as s/he cannot afford drugs ⁽¹⁹⁾. There is latent irreverence for the patient in the pharma hemisphere. General thinking “Oh well s/he was going to die sooner or later” but the shareholders should have high return on their investment. Mission accomplished. Irony is the patients put food on the table of all involved and gets no respect. 

On an anecdotal note in the hearing ⁽¹⁷⁾ companies claimed that they have their drug list prices are available on their websites. Good luck in trying to figure out prices of any drug! Fancy webpage designs but no prices. 

Under the current system bottom-line is that getting on the formulary, which gives preference to drug company and PBMs profits, is more important than the patient’s life and drug affordability. Question we need to ask FDA and others is why a generic drug that has been approved but has its availability controlled through formularies and not readily available at the local pharmacy. If US Congress has to tackle the juggernaut, so be it. My conjecture is that lobbyists will make sure that such simplicity does not happen. 

Meetings ⁽²⁰⁾ are held but nothing meaningful results. Each participant that includes brand and generic pharma companies, regulators and the supply chain participants have shared responsibility for the current woes of high/increasing drug prices and shortages. There is blame game. 

Lately drug companies have not introduced exceptionally better drugs than the current drugs at affordable prices ⁽⁹⁾. This is especially true for mass need diseases. To assure revenue growth, the easiest answer to revenue increase is to raise prices. It has become a habit. Once the existing blockbuster patents expire, I am not sure how pharma will continue their revenue growth. Over the long-term orphan drugs will not carry them over the finish line. 

There is a “creative destruction” solution ⁽²¹⁾ but everyone involved will make sure it never comes to fruition. In the simplest terms if a drug (brand or generic) has been approved by FDA, it should be readily available through a legitimate prescription at the local pharmacy or a web portal. Same drug e.g. ciprofloxacin could be manufactured by multiple FDA approved companies and be available at competitive prices through convenient outlets. There would be no preference between manufacturer “a” vs. “b” and there will be price competition. FDA’s approved drug list should be the formulary. There will be resistance.

What Does the Future Hold?

All said and done drug prices are going up and shortages are increasing. Every participant has contributed to high drug prices and shortages and no one wants to put on the yoke to make drugs affordable and eliminate shortages. It is not too late to fix the current landscape without government intervention which generally is brutal e.g. price fixing/controls.

To the pharmaceutical industry, issues and potential solutions are irrelevant because they are capitalizing on constant needs of patients who want to extend their life. They have tremendous opportunities to improve their profits and customer base ⁽¹⁰⁾. Instead of a revolution we have complacency. In the business world, “process of continuous improvement” is important but it seems like this philosophy has by-passed pharma as it is using its patients as pawns rather than competition to be profitable. 

Again, pharma and associates have to be proactive to reduce shortages and make drugs affordable while increasing their profits through “nondestructive creation”. It has to adopt better manufacturing technologies on its own volitions rather than being swayed by external influences. PBMs and associates need to adopt “nondestructive creation” and if they don’t “destructive creation” being considered ^{(22 )}could change the landscape. 

Pharmaceutical industry would not want government edicts to control shortages and control unscrupulous price increases. PBMs will also have to be reined in. Drug prices like Veteran’s Administration may have to be negotiated. US Legislators also have to wean off political influences to further their careers and serve the needs of the electorate. All this is a tall order and needs to be addressed rather than ignored. 

Girish Malhotra, PE

EPCOT International 

1. Malhotra, Girish: Impact of Regulations, Drug Manufacturing and Pharma Supply Chain (PBMs and allies) in Drug Shortages and Affordability 
2. PharmaCompasshttps://www.pharmacompass.com
3. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals? Profitability through Simplicity, August 17, 2010
4. Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay? Profitability through Simplicity, August 1, 2014 
5. Malhotra, Girish: A Blueprint for Improved Pharma Competitiveness, Contract Pharma, Vol. 16, 7, Pg. 46-49, September 2014
6. Malhotra, Girish: Comparison of Drugs Prices: US vs. India; Their Manufacturing Costs & Opportunities to Improve Affordability, Profitability through Simplicity, January 18, 2018
7. Berndt, Ernest R., Conti, Rena M. and Murphy, Stephen J: The Generic User Fee Amendments: An Economic Perspective, NBER Working Paper 23642, August 2017
8. Kim, Chan W., Mauborgne: Nondisruptive Creation: Rethinking Innovation and Growth, MITSloan Review, February 21, 2019
9. Schumpeter, Joseph:Capitalism, Socialism and Democracy, 1942, Accessed November 29, 2018
10. Malhotra, Girish: An Alternate Look at the Pharmaceutical World Revenues and Drug Affordability, Pages 2-5, www.gmpnews.net, Autumn 2017, Manufacturing Chemist, Volume 88, Number 10, October 2017, Pg. 28-32
11. Malhotra, Girish: The Path Towards Continuous Processing, Pharmaceutical Processing, August 2010, pgs 16-20
12. Malhotra, Girish: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, Profitability through Simplicity, March 20, 2017
13. Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg 12-13
14. Malhotra, Girish:  Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
15. Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes, Profitability through Simplicity, July 20, 2017, American Pharmaceutical Review, Vol. 20 Issue 6 September/October 2017 pgs. 86-91, Contract Pharma, Nov./Dec. 2017 pgs 56-58, Chemistry Today, November/December 2017, Vol. 35(6) pgs 62-65
16. Field of Dreams
17. Senate Finance Hearing on Drug Pricing, C-SPAN, February 26, 2019 
18. Langreth, Robert, Ingold, David, Gu, Jackie: The Secret Drug Pricing System Middlemen Use to Rake in Millions, Bloomberg News, September 11, 2018
19. Malhotra, Girish: Drug Prices: Food vs. Medicine - A Difficult Choice for Some, Profitability Through Simplicity, June 17, 2011
20. Malhotra, Girish: Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution, Profitability through Simplicity, December 7, 2018
21. Malhotra, Girish: Improving Drug Affordability for the United States Populous through Alternate  Business Models, Profitability through Simplicity, May 4, 2018
22. Malhotra, Girish: Could Amazon (A), Berkshire Hathaway (B) and J.P. Morgan Chase (M) be the Anti-Ballistic Missile (ABM) needed to Control/Curb Rising Healthcare Costs? Profitability through Simplicity,February 9, 2018

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