Addressing Blind Spots In Assuring Therapeutic Equivalence
By Ajaz S. Hussain, Ph.D., independent subject matter expert

Over the past decades, efforts to foster holistic healthcare and good pharmaceutical practices have centered on integrating design thinking and system-based approaches. However, their implementation during the COVID-19 pandemic revealed significant gaps, failing to deliver a unified public health response. As the incoming U.S. administration takes office, addressing systemic challenges in healthcare delivery and restoring public trust in pharmaceutical regulatory oversight is critical. The new FDA commissioner-designee's focus on Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health1 offers a timely opportunity to examine these gaps in ways that can expose root causes and cascaded assumptions that have been normalized in practice and distinguish between "special" and "common" causes of deviation and variability in public health and regulatory oversight.
One indicator of concern regarding the FDA's ability to generate needed assurances is when the Pentagon starts independent generic drug safety tests.2 This raises fundamental questions: Why is the DOD seeking independent drug testing, and why do they wish to explore quality scoring? Why isn't FDA approval sufficient? This commentary explores whether these actions reflect isolated issues (special causes) or suggest systemic vulnerabilities (common causes) within the current regulatory framework.
Background
At the turn of the century, errors in healthcare and pharmaceutical systems demanded urgent solutions.3,4 The FDA responded in the context of manufacturing quality with initiatives emphasizing real-time process control through process analytical technology (PAT), quality-by-design methodologies for pharmaceutical development, and system-based quality management. More recent reports, such as the 2019 National Academies of Sciences, Engineering, and Medicine's A Design Thinking, Systems Approach to Well-Being Within Education and Practice,5 reinforce this need for design thinking and system approaches — we struggle to practice despite extensive education and training.
Frameworks such as Deming's theory of Profound Knowledge6 and Robert Kegan's Orders of Consciousness7 provide a pathway forward. These approaches emphasize adaptive, iterative learning with empathy and transitioning from externally driven compliance (socialized mind—a stage in adult development) to adaptive, self-transforming practices, which I have discussed extensively on Pharmaceutical Online.8-10 These principles underpin many FDA guidance documents, including those for process validation. In practice, however, what actually happens often differs from the established standards.
Chronic challenges in following practices one claims to be committed to, transparently demonstrating actions (via documentation), and effectively preventing errors raise fundamental questions about system maturity and trustworthiness. Public skepticism about FDA oversight has always existed. Still, it has intensified following the COVID-19 pandemic and is likely to intensify if we, a community of knowledge and practice, do not acknowledge errors and learn our lessons.
Is this skepticism now on seeking institutionalization, as evidenced by Valisure establishing a cooperative research and development agreement (CRADA) with the Department of Defense (DoD)11? This CRADA seeks ways to bring "much-needed transparency in drug quality" and to "enable conscientious manufacturers to be able to compete better and allow major purchasers of drugs, like the Department of Defense and Veterans Administration, to reward good manufacturers and exclude substandard medicines from being consumed by the military and veterans, and serve as a model for broader adoption throughout the United States to benefit all American patients."11 What about the public? What can and should the FDA do to bring much-needed transparency on quality and distinguish between conscientious and careless manufacturers?
Erosion Of Confidence: Special Or Common Cause?
The erosion of confidence in FDA oversight primarily stems from systemic issues inherent in and interactive with the regulatory routines - the "common cause challenge." While no system is perfect, crises occasionally arise from specific, identifiable failures or "special causes." Distinguishing between these causes is critical for implementing meaningful and sustainable reforms.
In the context of ensuring therapeutic equivalence, the history of systemic challenges is evident — from the generic drug scandal12 to the revelations in Bottle of Lies: The Inside Story of the Generic Drug Boom13 and the recent concern over the FDA's failure to inspect a drug manufacturing facility after seven recalls, one of which was potentially deadly.14 These recurring issues highlight a persistent common cause in our blind spot, hidden under assumptions cascaded down over decades since 1938, the enactment of the Federal Food, Drug, and Cosmetic Act, and are not easy to acknowledge. These deeper layers require probing questions and a comprehensive, strategic solution. The efforts by the FDA to identify and address blind spots in ensuring quality and therapeutic equivalence2,15 highlight the challenges involved in shifting from a typical approach that often concentrates on treating symptoms through "special cause" thinking instead of addressing systemic issues at their roots.
The establishment of the Office of Pharmaceutical Science (OPS) within the CDER in 1995 sought to address a legislative gap originating from the Federal Food, Drug, and Cosmetic Act of 1938. In retrospect, this legislation lacked specific provisions for crucial aspects of pharmaceutical (formulation and manufacturing) science in how the provisions for chemistry, manufacturing, and controls (CMC) were set and didn't evolve with advances in pharmaceutical science and technology, leaving interpretations by chemists as they saw what is needed from their perspective to test for quality, missing out on the multidisciplinary "team science" 16 considerations needed.2
In a border context, the FDA does not directly approve a drug [substance]; it evaluates the quality, safety, and efficacy of pharmaceutical dosage forms and drug substances — products combining active pharmaceutical ingredients (APIs) with inactive ingredients. This evaluation relies on NDAs or ANDAs, not new pharmaceutical (product) applications. Unlike regulatory systems in the European Union or Japan, the FDA resisted adopting pharmaceutical development reports to assess product quality during NDA or ANDA reviews. In part, the PAT initiative aimed to break this logjam.2 This "oversight," as in a blind spot, reflects on the mindset and subtly imposes a significant challenge that has persisted since the 1937 Elixir of Sulfanilamide tragedy caused by an "inactive ingredient" — which, ironically, the FDA still calls the "Sulfanilamide Disaster."17 Such vulnerabilities continue to impact regulatory frameworks, as highlighted in a December 2002 media headline, "Prescription for Trouble: How a Flaw in FDA's Safety Net May Pose a Risk to the Public with Generic Drugs."18
Underpinning the "prescription for trouble" is a failure to appreciate a significant pharmaceutical formulation difference (i.e., pharmaceutical inequivalence between a "microemulsion" and a solubilized solution formulation), a mindset that a "pivotal biostudy" trumps other elements of therapeutic equivalence assessment. For instance, in this case, the "cherry-picked" bioequivalence trial design in the ANDA didn't align with the product use instruction in the reference-listed drug product (RLD) labeling. Cherry-picked? Yes, until the regulations were changed, and decades later, sponsors could legally choose a "passing" study (disregarding "failed" studies) to include in a regulatory application.
More than two decades before the COVID-19 pandemic, the microemulsion challenges were a wake-up call for the CDER FDA. To what extent was this lesson appreciated in the Center for Biologics Evaluation and Research? This is not a settled issue, and in science, nothing is "settled." The new FDA commissioner, I expect, will need to question the formulation and stability basis for lipid nanoparticles, particularly regarding their manufacturing quality and equivalent/interchangeability in vaccines.
Note that the generic label is legally required to be the same as RLD, and this provision can occasionally interact with variations in pharmaceutical equivalence and bioequivalence in confusing ways and invoke the perception of fraud. For instance, before the FDA proposed to withdraw approval for two generic versions of Concerta (methylphenidate hydrochloride ER)19, the approved labels for these generic products copied the pharmacokinetic profile of the reference-listed drug, which had a unique osmotically programmed pharmacokinetic profile. Although few patients typically pay attention to the package insert, some did in this case (see Voices of/for Patients20).
What about healthcare professionals? Are they still in a blind spot? "We can be blind to the obvious, and we are also blind to our blindness." — Daniel Kahneman.
Additional Independent Testing: Symptom Or Solution?
The rise of independent testing companies like Valisure reflects a societal response to significant market failures in the generic drug sector—this additional need, despite the availability of market standards as in compendial monographs. It raises critical questions: Is additional independent testing, as in Valisure, addressing isolated issues or symptomatic of more profound systemic blind spots within a regulatory framework struggling to keep pace with evolving complexities in pharmaceutical manufacturing? For instance, “it is FDA-approved, and the process is validated, so if I don't look, there is no problem.”9 Recognizing and addressing systemic vulnerabilities and market-driven failures is essential to determining whether independent testing is a temporary fix or part of a sustainable solution.
A lack of transparency in quality assurance, combined with intense cost pressures and approval challenges faced by the industry and the FDA, has created a race to the bottom. This situation often overlooks past mistakes and gaps in knowledge across the board, including narrow therapeutic index (NTI) drug products,21,22 which contributes to compromised assurance, suboptimal and deviant manufacturing practices, and recurring external failures and drug shortages in the United States.
Totality Of Evidence For Therapeutic Equivalence
Regulatory oversight must transition from a narrow reliance on "pivotal bio studies" to a more comprehensive totality-of-evidence approach: a phrase typically invoked in complexity, as in the biosimilar context. In a broader context, this phrase emphasizes a systems approach: multidimensional and interactive considerations for therapeutic equivalence and its assurance, not just in part but in totality. This framework requires applying appropriate, risk-informed weighting to all components of therapeutic equivalence, including pharmaceutical equivalence, cGMP compliance, labeling, and bioequivalence. Transparent articulation of these weights is critical for fostering public confidence and enabling robust statistical process control (SPC) practices espoused in the FDA guidance on process validation23, along with the statistically sound interpretation of variations, regulatory specifications, and process stability and capability2 that ensure continued therapeutic equivalence assurance throughout a product's life cycle.
As smart manufacturing practices (as in, for instance, self-monitoring, analyzing tools) proliferate to usher in the digital pathway to manufacturing excellence to making manufacturing predictive and adaptive24 in smart factories, a new standard of evidence of real-world sameness – evidence of process stability and capability will become "current" — the "c" in cGMP. Much of the generics sector will inevitably follow, albeit slower. To provide evidence (and not just opine therapeutic equivalence), the entire industry must now adhere to the rigorous evidentiary principles and practices of process validation per the FDA's guidance in January 2011. To achieve this, the FDA’s cGMP functions must be appropriately empowered and resourced to seamlessly align with ANDA review processes and leverage “pre-approval inspections” to address legacy disparities and ensure effective knowledge transfer, robust process validation, and continued process verification. With routine cGMP inspections and Annual Product Reviews, the industry and FDA can confer the assurance with evidence of therapeutic equivalence over the commercial lifespan of pharmaceutical products.
A totality-of-evidence approach provides a sustainable framework for all [generic] drug products. It integrates key elements — pharmaceutical equivalence, cGMP compliance, labeling, and bioequivalence — while emphasizing the importance of life cycle management. This methodology underpins robust design, development, and process validation practices, ensuring therapeutic equivalence is attained at approval and (evidently) maintained over time.
To transcend isolated fixes, the framework must incorporate advanced AI tools, recalibrate incentives, and enhance quality metrics. Leveraging predictive quality metrics and embracing cross-functional collaboration can further strengthen oversight. Advanced technologies, such as AI-driven analytics and real-time monitoring, improve transparency, detect anomalies, and ensure data integrity while providing actionable insights for decision-making.
A totality-of-evidence approach aligns regulatory oversight with the complexities of a rapidly evolving pharmaceutical industry, enabling regulatory frameworks to become mature, adaptive systems. These systems can address current challenges and anticipate and mitigate future risks, ensuring public trust in therapeutic equivalence and safeguarding the resilience of the pharmaceutical supply chain.
Conclusion
The erosion of confidence in the FDA, and in public health more broadly, stems from common systemic issues that reveal collective blind spots. Addressing these challenges requires recognizing the inherent unpredictability of chaotic systems24 and understanding that their outcomes are shaped by initial conditions: our actions, new drug applications, analytical and manufacturing technologies, and raw materials — both “active” and “inactive” ingredients. Not doing so is a systemic blind spot observed and illuminated here from the viewpoint of pharmaceutical science, as in the historical Office of Pharmaceutical Science at the FDA. Therapeutic equivalence between clinical lots and commercial lots of new and generic drugs is the foundation upon which we ground claims of safety, efficacy, and later effectiveness in the real world. It is essential to prevent cascading assumptions from becoming continuous blind spots that overshadow our efforts and goodness. The totality of evidence considered broadly is at the heart of adopting a systems perspective; in doing so, we can systematically identify and address the root causes of variability, moving from reactive responses to proactive strategies that foster continual improvement.
References
- Marty Makary. Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health. September 17, 2024, Bloomsbury Publishing.
- Pentagon starts independent generic drug safety tests, by Adriel Bettelheim. August 8, 2023. Axios News.
- Institute of Medicine (US) Committee on Quality of Healthcare in America. To Err is Human: Building a Safer Health System. Kohn LT, Corrigan JM, Donaldson MS, editors. Washington (D.C.): National Academies Press (U.S.); 2000. PMID: 25077248.
- U.S. FDA White Paper: Innovation and continuous improvement in pharmaceutical manufacturing: pharmaceutical cGMPs for the 21st century. The PAT team and manufacturing science working group report: A summary of learning, contributions, and proposed next steps for moving toward the "desired state" of pharmaceutical manufacturing in the 21st century. September 2004. https://wayback.archive-it.org/7993/20170405121836/https://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4080b1_01_manufSciWP.pdf. Accessed January 6, 2025.
- National Academies of Sciences, Engineering, and Medicine. 2019. A Design Thinking, Systems Approach to Well-Being Within Education and Practice: Proceedings of a Workshop. Washington, D.C, The National Academies Press. https://doi.org/10.17226/25151.
- The Deming System of Profound Knowledge (SoPK) - The W. Edwards Deming Institute.
- In Over Our Heads: The Mental Demands of Modern Life. By Robert Kegan — Harvard University Press (1998).
- Compliance or Adherence How To Approach cGMP Regulations In The 21st Century (September 22, 2016)
- How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen) (September 18, 2017).
- Hussain, A.; Deploy AI To Become A cGMP "Special Agent" With A License To Care, Pharmaceutical Online, January 7, 2025.
- VALISURE SIGNS AGREEMENT WITH DEPARTMENT OF DEFENSE TO INDEPENDENTLY TEST & QUALITY SCORE DRUGS (News provided by Valisure. August 8, 2023, 06:00 ET).
- Garth, B., Lixin, Y., Liang, H., and Qiang, Z. Development of the generic drug industry in the U.S. after the Hatch-Waxman Act of 1984. Acta Pharmaceutica Sinica B. Volume 3, Issue 5, September 2013, Pages 297-311.
- Bottle of Lies: The Inside Story of the Generic Drug Boom, by Katherine Eban. May 14, 2019. Ecco.
- FDA Hasn't Inspected This Drug Factory After 7 Recalls, 1 Potentially Deadly — ProPublica, by Patricia Callahan, Debbie Cenziper and Megan Rose. December 12, 2024.
- FDA White-Paper--FDA-Pharmaceutical-Quality-Oversight.pdf (2013)
- Hussain, A.S., Morris, K. & Gurvich, V.J. Pharmaceutical Quality, Team Science, and Education Themes: Observations and Commentary on a Remarkable AAPS PharmSciTech Theme Issue. AAPS PharmSciTech 22, 88 (2021). https://doi.org/10.1208/s12249-021-01970-7
- Sulfanilamide Disaster | FDA (Accessed January 6, 2025).
- Prescription for trouble/How flaw in FDA safety net may pose a risk to the public with generic drugs. By Tom Abate, Todd Wallack, Chronicle Staff Writers. December 22, 2002
- Methylphenidate Hydrochloride Extended Release Tablets (generic Concerta) made by Mallinckrodt and Kudco | FDA (Accessed January 6, 2025).
- Voices of/for Patients by Ajaz S. Hussain, Reactions to the November 13 FDA Action on Generic Methylphenidate ER tablets; a sample from two popular blogs. November 15, 2014.
- Hussain, A.S., Gurvich, V.J. & Morris, K. Pharmaceutical "New Prior Knowledge": Twenty-First Century Assurance of Therapeutic Equivalence. AAPS PharmSciTech 20, 140 (2019). https://doi.org/10.1208/s12249-019-1347-6
- Physicochemical failure modes for first-line therapy Narrow Therapeutic Index (NTI) drugs: a call for attention NTI risk classification and New Prior Knowledge. By Dr. Ajaz Hussain, Dr. Harsh S. Shah, Dr. Kaushalendra Chaturvedi, and Dr. Kenneth Morris. European Pharmaceutical Review. July 2, 2021.
- FDA Guidance for Industry, Process Validation: General Principles and Practices, January 2011.
- Digital Plant Maturity Model 3.0 - BioPhorum
- Hussain, A.S. Chaos to Continual Improvement: Path to Harmonization. In CPhI Industry Report, New modalities, new methods and new thinking to solve old problems, 2019.
About The Author:
Ajaz S. Hussain, Ph.D., is a pharmaceutical quality and regulatory science expert with decades of experience across academia, industry, and government. As a former deputy director of the FDA's Office of Pharmaceutical Science, he was pivotal in pioneering initiatives like the process analytical technology (PAT) framework and the Pharmaceutical Quality for the 21st Century Initiative. Hussain also served as president of the National Institute for Pharmaceutical Technology and Education (NIPTE), advancing pharmaceutical technology and regulatory science. Now an independent consultant, he empowers organizations to integrate design thinking with a systems approach to advance innovative technologies that hold high potential for enhancing patient care and operational excellence.