Random Thought

𝐑𝐚𝐧𝐝𝐨𝐦 𝐭𝐡𝐨𝐮𝐠𝐡𝐭: Want to sell pharmaceuticals in the U.S.? The government should require that 𝐚𝐥𝐥 such entities develop a ‘𝐦𝐚𝐧𝐮𝐟𝐚𝐜𝐭𝐮𝐫𝐢𝐧𝐠 𝐚𝐧𝐝 𝐬𝐮𝐩𝐩𝐥𝐲 𝐜𝐡𝐚𝐢𝐧 𝐝𝐢𝐠𝐢𝐭𝐚𝐥 𝐭𝐰𝐢𝐧’ for their operations. A standard model to be developed (in cooperation with pharmaceutical manufacturers, etc.) by NIST who will define the data elements, etc., definitions, metrology/measurement, information collection, reporting, technology used, etc., etc. 

Data from the various manufacturers’ digital twins would regularly (e.g. daily) ‘feed’ a government-controlled ‘𝐩𝐡𝐚𝐫𝐦𝐚 𝐢𝐧𝐝𝐮𝐬𝐭𝐫𝐲 𝐦𝐚𝐧𝐮𝐟𝐚𝐜𝐭𝐮𝐫𝐢𝐧𝐠 𝐚𝐧𝐝 𝐬𝐮𝐩𝐩𝐥𝐲 𝐜𝐡𝐚𝐢𝐧 𝐝𝐢𝐠𝐢𝐭𝐚𝐥 𝐭𝐰𝐢𝐧.’ 

This will require enabling legislation e.g. to overcome manufacturer claims of proprietary information, trade secrets, etc. that they historically have used to not provide information. A wide variety of “carrots” and "sticks" will need to be used to gain industry cooperation, for example the government underwriting the costs of development, deployment, and implementation, with the benefits of having such a system accruing to the manufacturers. 

Once the FDA’s QMMP is deployed to manufacturers its data can then also be folded into the digital twin. With the resulting complete transparency and end-to-end visibility across the entire industry now available to the government (manufacturing information, quality information, supply chain information, etc.), the use of AI, ML, and other such tools should support the ability to forecast and anticipate problems, issues, disruptions, etc. so that the appropriate efforts at prevention, mitigation, etc. can be carried out successfully.

6-part article of which the above is a sub-part

Drug Shortages - Part VI (Putting It All Together)

Putting it all together:

The Framework Elements: 

I - Development/Implementation of New Capacity and Capabilities

II - FDA Quality Program

III - Transparency & End-to-End Visibility

IV - Ongoing Oversight and Reaction

V - Overall Coordination of Efforts

Drug Shortages - Part V (Coordination of Efforts)

Note: This article is the fifth entry of a series of mind maps listing actions that can be taken in various areas, that if/when taken and implemented collectively can contribute to systematically improving the situation.

Framework Needed:

I - Development/Implementation of New Capacity and Capabilities

II - FDA Quality Program

III - Transparency & End-to-End Visibility

IV - Ongoing Oversight and Reaction

V - Overall Coordination of Efforts

VI - Putting It All Together

Drug Shortages - Part IV (Reaction)

Note: This article is the fourth entry of a series of mind maps listing actions that can be taken in various areas, that if/when taken and implemented collectively can contribute to systematically improving the situation.

Framework Needed:

I - Development/Implementation of New Capacity and Capabilities

II - FDA Quality Program

III - Transparency & End-to-End Visibility

IV - Ongoing Oversight and Reaction

V - Overall Coordination of Efforts

VI - Putting It All Together

Drug Shortages - Part III (Transparency & End-to-End Visibility)

Note: This article is the third entry of a series of mind maps listing actions that can be taken in various areas, that if/when taken and implemented collectively can contribute to systematically improving the situation.

Framework Needed:

I - Development/Implementation of New Capacity and Capabilities

II - FDA Quality Program

III - Transparency & End-to-End Visibility

IV  Ongoing Oversight and Reaction

V - Overall Coordination of Efforts

VI - Putting It All Together

Drug Shortages - Part II (Quality Program)

Note: This article is the second entry of a series of mind maps listing actions that can be taken in various areas, that if/when taken and implemented collectively can contribute to systematically improving the situation.

Framework Needed:

I - Development/Implementation of New Capacity and Capabilities

II - FDA Quality Program

III - Transparency & End-to-End Visibility

IV - Ongoing Oversight and Reaction

V - Overall Coordination of Efforts

VI - Putting It All Together

Update: Interesting development: Valisure and DoD Signed a Cooperative Research & Development Agreement to Conduct a Pharmaceutical Quality Risk Assessment Pilot Study https://www.prnewswire.com/news-releases/valisure-signs-agreement-with-department-of-defense-to-independently-test--quality-score-drugs-301895301.html

Drug Shortages - Part I (New Capacity and Capability)

Background: Drug shortages are back in the news. This time it is a shortage of some essential cancer-fighting drugs such as cisplatin and carboplatin, see: FDA allows temporary import of unapproved Chinese cancer drug to ease U.S. shortage. Although there are multiple factors that can occur to cause drug shortages (see the list of possible causes I put together in 2002 with contemporaneous examples, republished on my blog in 2011 and on LinkedIn in 2015.), in this case the issue was caused by an Indian manufacturer (Intas) halting production at one manufacturing site following the discovery of quality deficiencies during an FDA inspection. This then snowballed, threatening lives, and leading to the FDA's emergency approval of the import of 'unapproved' versions of the drugs from China. 

According to the New York Times - Drug Shortages Near an All-Time High, Leading to Rationing - "The shortages are so acute that they are commanding the attention of the White House and Congress, which are examining the underlying causes of the faltering generic drug market, which accounts for about 90 percent of domestic prescriptions. The Biden administration has assembled a team to find long-term solutions for shoring up the pharmaceutical supply chain..." Unfortunately, we have heard this many times before. For example in 2018, the FDA (once again) put together a drug shortages task force to produce solutions. I expressed skepticism at the time!

It's long been clear to me that there has been a market failure and that a root cause for many of our drug shortage problems is that the segment of our drugs ("old," long-available, off-patent and generic sterile injectable drugs) that are disproportionately responsible for drug shortages are priced too low. As such, the usual 'article of faith' that is so often served up as a supposed solution to the issue (example from the NYT, 2017) i.e. "Increasing the number of competitors for a given drug in the marketplace will also help prevent and mitigate future shortages" is nonsensical!

The below, from January 2018, is exactly why we just have had the availability issues for cisplatin and carboplatin!

Unfortunately, as I observed, a solution that requires higher prices is not very palatable. The fact is that many (most) people think of drug manufacturers as a monolith, instead of recognizing that there are distinct segments that operate under very divergent conditions. In February 2019 I asked the question: "Drug pricing- is there a topic more fraught with simplism in this day and age?" Unfortunately, the answer was and continues to be "no!"

The bottom line? We will need to eschew simplistic thinking if we are to make any lasting progress in this area. Additionally, looking to the FDA to come up with a solution is flat out wrong. The solution to decreasing the frequency of drug shortages and mitigating their effects is multifactorial and will require a 'Whole of Government' approach that also includes collaboration and partnerships with industry, scientific organizations, public-private partnerships, academic organizations, and non-profits.

Note: This article is the first entry of a series of mind maps listing actions that can be taken in various areas, that if/when taken and implemented collectively can contribute to systematically improving the situation. First up, we need to improve pharmaceutical manufacturing capacity and capability!

Framework Needed:

I - New Capacity & Capability - the development and implementation of needed new capacity (e.g. plant, inventory) and new capabilities (e.g. advanced manufacturing technology) for drug manufacturing:

II - FDA Quality Program

III - Transparency & End-to-End Visibility

IV - Ongoing Oversight and Reaction

V - Overall Coordination of Efforts

VI - Putting It All Together

Random charts - drug deaths

 

Overdose Death Rates - Trends and Statistics

Random chart - drug discovery

Source: Academia and industry: allocating credit for discovery and development of new therapies

Random charts - FDA

Source: The FDA’s Drug Pricing Strategy: What’s New?

"...To help track the FDA’s progress in implementing its strategy, we’ve created a timeline of the major announcements and regulatory actions the agency has taken to encourage a competitive market for biologic drugs, address drug shortages and abuses of the FDA’s citizen petition process, and streamline the Risk Evaluation and Mitigation Strategies (REMS) program, which aims to promote timelier competition from generic drug manufacturers. We’ll be updating this periodically. In a future post, we’ll discuss additional steps the agency and Congress could take to lower drug prices..."

Random chart - CAR-T

Source: The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL (9-pg PDF)

Random charts - peds drugs

Source: Nonclinical Safety Testing in Support of Development of Paediatric Medicines: Core Guideline  (38-page PDF)

Random charts - orphan drugs

Source: ORPHAN DRUGS: FDA Could Improve Designation Review Consistency; Rare Disease Drug Development Challenges Continue (45-pg PDF)

Random charts - opiods

Source: Changing dynamics of the drug overdose epidemic in the United States from 1979 through 2016

"... The U.S. drug overdose epidemic has been inexorably tracking along an exponential growth curve since at least 1979. Although there have been transient periods of minor acceleration or deceleration, the overall drug overdose mortality rate has regularly returned to the exponential growth curve. This historical pattern of predictable growth for at least 38 years suggests that the current opioid epidemic may be a more recent manifestation of an ongoing longer-term process. This process may continue along this path for several more years into the future. Paradoxically, there has been substantial variability with which specific drugs have become dominant in varying populations and geographic locales. This variability all but negates the possibility of confident predictions about the future role of specific drugs. Indeed, it is possible that a future overdose epidemic may be driven by a new or obscure drug that is not among the leading causes of drug overdose death today. Understanding the forces that are holding multiple sub-epidemics together onto a smooth exponential trajectory may be important in revealing, and effectively dealing with, the root causes of the epidemic..."

Random charts - drug diversion

 

Source: Drug Diversion Digest: 2018 Six Month Retrospective: 18.7M Pills Lost Due to Healthcare Employee Misuse and Theft

"The first half of 2018 proved that clinical drug diversion continues to threaten the ability of healthcare organizations to provide high-quality patient care and to ensure safe medication administration... Our analysis is based on 179 total incidents of medication tampering, fraud, and theft reported in the news from January 1, 2018 through June 30, 2018. We know that this aggregation reflects just the tip of the iceberg, representing only a limited set of diversion events carried out by healthcare workers during this time period..."

Random chart - generic profits

Source: Teva Plunges as U.S. Sales Drop Amid Generic Price Erosion

"... Teva Pharmaceutical Industries Ltd. plummeted the most in six months after U.S. sales fell amid price erosion for generic drugs, the company’s biggest business. The 18 percent slump in overall second-quarter sales to $4.7 billion trailed analysts’ average estimate and was led by a decline in sales of copycat drugs in North America. Rapid approvals for generic medicines and consolidation of big pharma buyers continued to squeeze industry profitability for a second year..."

Random charts - drug industry

Source: Drug Industry: Profits, Research and Development Spending, and Merger and Acquisition Deals (73-pg GAO PDF)

Random charts - CAR-T

Source: Chimeric Antigen Receptor T-Cell Therapy for B-Cell Cancers: Effectiveness and Value (126-pg PDF)

Random chart - profitability

Source: Health care profits concentrated at drug companies

"Ninety-nine of the largest publicly traded health care companies cumulatively collected $33 billion of profit and $577 billion of revenue worldwide in the third quarter this year, according to earnings reports we tracked. Pharmaceutical companies collected more than 60% of those profits, but only 22% of the revenu."

Random charts - Afghan opium

 

Source: Afghanistan: Opium Survey 2015 (12-page PDF)