United States FDA Introduces a New Initiative
Readers may be familiar with the words of FDAs Janet Woodcock, MD, in the early 2000s, calling for:
“A maximally efficient, agile, flexible pharmaceutical manufacturing sector without extensive regulatory oversight.”
For those still to be acquainted with Dr Woodcock and her work on regulatory modernization, while director at the Center for Drug Evaluation and Research (CDER), the following background may be of interest.
In February 2003, Docket No. 03N-0059 was posted on the US Federal Register, announcing a new FDA initiative titled:
“Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach; Establishment of a Public Docket” [1]
The SUMMARY begins:
“The Food and Drug Administration (FDA) is announcing that it is establishing a public docket for information relevant to the agency’s current good manufacturing practice (CGMP) initiative concerning the regulation of pharmaceutical manufacturing and product quality.”
August 2004 saw the final Report published. [2]
Also in 2004, the FDA launched the Critical Path Initiative. [3]
The aim was described as follows:
“The Critical Path Initiative (CPI) is FDA’s strategy to drive innovation in the scientific processes through which medical products are developed, evaluated, and manufactured.”
The Executive Summary of the full report, titled Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products,[4] begins:
“This report provides the Food and Drug Administration’s (FDA’s) analysis of the pipeline problem — the recent slowdown, instead of the expected acceleration, in innovative medical therapies reaching patients.” It concludes:
“Through scientific research focused on these challenges, we can improve the process for getting new and better treatments to patients. Directing research not only to new medical breakthroughs, but also to breakthrough tools for developing new treatments, is an essential step in providing patients with more timely, affordable, and predictable access to new therapies. We are confident that, with effective collaboration among government, academia, and the private sector, these goals can be achieved.”
What Happened Next?
In November 2006, the US Government Accountability Office issued a report titled “NEW DRUG DEVELOPMENT: Science, Business, Regulatory, and Intellectual Property Issues Cited as Hampering Drug Development Efforts”[5]
The rationale for the study was explained:
“Drug development is complex and costly, requiring the testing of numerous chemical compounds for their potential to treat disease. Before a new drug can be marketed in the United States, a new drug application (NDA), which includes scientific and clinical data, must be approved by the Food and Drug Administration (FDA). Recent scientific advances have raised expectations that an increasing number of new and innovative drugs would soon be developed to more effectively prevent, treat, and cure serious illnesses. However, industry analysts and the FDA have reported that new drug development, and in particular, development of new molecular entities (NMEs)—potentially innovative drugs containing ingredients that have never been marketed in the United States—has become stagnant.”
The report presents data on drug development attrition rates and time to market. Page 8 of the report contains some sobering statistics.
Attrition rates are reported as:
- 10,000 screened molecules (from the patent portfolio).
- 250 enter nonclinical testing (development candidates).
- Five pass on into clinical trials (245 out of 250 fail)
- One is approved for sale (four out of five fail)
Development timelines are reported as:
- Nonclinical phase = approximately 3 years
- Clinical phase = 7 years
- NDA review and approval = 1.5 years
- Total Time to Market = 11.5 years
“It is crucially important that readers are clear that these statistics relate to supply chain failure. Not to sound like a broken record, but it is the product of the supply chain that is evaluated by a regulatory authority. It is also the product of the supply chain that enters a patient’s body. For the first time, there was real-world data and published evidence highlighting the failure rates and slothful time to market in the pharmaceutical supply chain. It would seem reasonable to believe that the warning bell sounded by the GAO report would have led to loud ringing of klaxons within the pharmaceutical community. That does not appear to be the case.”
So, as far back as late 2006, there was unequivocal evidence that all was not as it as it should have been in the pharmaceutical supply chain.
The following year, patient safety was cruelly impacted.
The Heparin Tragedy
In 2007 – 8, economically motivated adulteration hit the news, when a toxic ingredient was found in heparin (a blood-thinning agent) supplied by Baxter. It resulted in shocking injuries for unsuspecting patients. Investigators discovered that Baxter had procured raw materials from a rogue source. The source saved cost by using an ingredient that was 100 times cheaper than the authentic material. It turned out to be a toxic substance. Suddenly, the industry was awash with concerns over the prospect of economically motivated adulteration in the pharmaceutical supply chain.
After the incident, the Pew Charitable Trust released an excellent, in-depth report titled After Heparin.[7]
This is the PEW HEALTH GROUP summary:
“In late 2007, US health officials began receiving reports of unexpected allergic-type reactions in patients undergoing dialysis. The reactions were linked to a widely used blood thinner—heparin—and specifically to an adulterant that had been introduced during manufacture of the drug in China. The US Food and Drug Administration (FDA) believes the adulteration of heparin was an economically motivated act—a clear breach of the US pharmaceutical supply chain. “Pharmaceutical manufacturers and distributors work together in a robust system to deliver high-quality products, but drug manufacturing and distribution have become increasingly complex in recent years. Prescription and over-the-counter (OTC) medications originate in factories all over the world, moving into the American marketplace through supply chains that can involve numerous processing plants, manufacturers, suppliers, brokers, packagers, and distributors. “The number of drug products made outside of the United States doubled from 2001 to 2008, according to FDA estimates.
The FDA estimates that up to 40 percent of finished drugs used by US patients are manufactured abroad, and 80 percent of active ingredients and bulk chemicals used in US drugs come from foreign countries. Increasingly, the United States relies on drug manufacturing in developing countries—mainly China and India. Globalization, increased outsourcing of manufacturing, the complexity of pharmaceutical distribution, and the existence of criminal actors willing to capitalize on supply chain weaknesses has created the potential for counterfeit or substandard medicines to enter the system and reach patients. As evidenced by the adulteration of heparin and other case studies outlined in this report, these rare but potentially serious events can have grave consequences.”
In addition to economic adulteration, other supply chain issues began to emerge. These typically appeared under the categories of shortages, counterfeiting, and cargo diversion or theft.
What was happening in the pharmaceutical supply chain and how were the issues being addressed?
In PART 2, we will investigate the root cause issues that preceded what we now know about the pharmaceutical supply chain.
[1] Pharmaceutical Current Good Manufacturing Practices for the 21st Century: A Risk-Based Approach; Establishment of a Public Docket, Department of Health and Human Services, Food and Drug Administration. [Docket No. 03N-0059]https://www.federalregister.gov/documents/2003/02/27/03-4568/pharmaceutical-current-good-manufacturing-practices-for-the-21st-century-a-ri, Accessed 05/17/2025
[2] PHARMACEUTICAL CGMPS FOR THE 21ST CENTURY — A RISK-BASED APPROACH FINAL REPORT: https://www.fda.gov/media/77391/download Accessed 05/17/2025
[3] FDA’s Critical Path Initiative: http://wayback.archive-it.org/7993/20180125035414/https:/www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/ucm076689.htm Accessed 05/17/2025
[4] Innovation or Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products, U.S. Department of Health and Human Services, Food and Drug Administration, March 2004. http://wayback.archive-it.org/7993/20180125032208/https://www.fda.gov/ScienceResearch/SpecialTopics/CriticalPathInitiative/CriticalPathOpportunitiesReports/ucm077262.htm Accessed 05/17/2025
[5] New Drug Development: Science, Business, Regulatory, and Intellectual Property Issues Cited as Hampering Drug Development Efforts, GAO-07-49Published: Nov 17, 2006: https://www.gao.gov/products/gao-07-49 Accessed 05/17/2025
[7] http://www.pewtrusts.org/en/research-and-analysis/reports/2011/07/12/after-heparin-protecting-consumers-from-the-risks-of-substandard-and-counterfeit-drugs