Comment posted for Public Health Focused Essential Meds, MCM and Their Critical Inputs List to Address Section 3(c) of EO 13944(1)

FDA posted List of Essential Medicines, Medical Countermeasures, and Critical Inputs as they are required by the executive order. 

By providing a list, it is good to see FDA has done some constructive work to alleviate essential drugs. My rating on a scale of ONE to TEN is about TWO. WHY? My explanation is as follows. 

 

Significant work is and would be needed to produce the identified drugs. Following questions need to be addressed. I am not sure if FDA has any capability or the expertise to address any of the questions. 

 

That being said without a timetable set by the US Government, we should not expect much or be ready for a long time unless someone has better ideas. 

 

We should not be surprised if any of the needed APIs are NOT manufactured in the United States. If they were, we would not have shortages. Based on how much API is needed to produce large dosages, one should not be surprised that any company opting to produce these drugs would be challenged. 

 

There are many hurdles/obstructions to the list. The task is not going to be easy. All of the following questions need to addressed. Significant concerted effort https://bit.ly/3nxOlIz ⁽²⁾ is needed.   

 

Following information would be needed. 

 

1.     What are the quantities needed for each API? 

2.     Has anyone at FDA spent time to figure out where the needed raw materials for API will come from? Most likely the needed raw material are not manufactured in the United States.  

3.     If there are plants in US do they have the necessary and adequate equipment and trained personnel to produce any of these APIs? 

4.     Since these APIs are not produced at any of the US based plants what kind of ANDA approval time would be needed from FDA. Is it going to be its routine 36-48 months? Is so, the basic need to have these drugs readily available would be defeated. Unless FDA alters its current practice from 36-48 months to 90 day approval http://bit.ly/33SiqHS ⁽³⁾ not much will change. It is possible to make the change but effort would be needed and that includes mindset at FDA. 

5.     Do the companies who opt to produce these APIs in the United States have the processes that are economic to meet the price constraints PBMs put on the suppliers? One has to remember that unless PBMs make their required or necessary margins they will not distribute these drugs in the United States. Would the API producers be able to make their margins in light of PBM constraints? 

6.     In FDA’s proposal it keeps on touting that “Advanced Manufacturing” will or can alleviate COULD reduce shortages. Irony is that FDA has never tested whatever they call “advanced” on a commercial scale for any product. FDA does not have the manpower that is experienced to test any of what they call “Advanced Manufacturing”.  Their feasibility and economics have never been put to test. There is HUGE difference between what works in the laboratory and what works on a commercial environment. 

 

Based on the bureaucracy of FDA which it wants to protect at every cost, just publishing this list is nice effort but unless there is government edict or API producing companies have huge financial incentive not much will happen with respect to drug shortages of essential drugs. 

 

Girish Malhotra, PE

EPCOT International

 

1.     https://www.federalregister.gov/documents/2020/08/14/2020-18012/combating-public-health-emergencies-and-strengthening-national-security-by-ensuring-essential

2.     Malhotra, Girish: A road map for driving pharmaceutical manufacturing back to the USA by 2025, Profitability through Simplicity October 6, 2020 Accessed November 2, 2020 

3.     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 November 2, 2020

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

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

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

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

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

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

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

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

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

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

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

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

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

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

What would the Showstoppers say or think? 

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

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

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

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

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

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

Girish Malhotra. PE

EPCOT International

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

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

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