What is the approval history and clinical development pathway of Insulin?

Introduction to Insulin

Discovery and Early Use
Insulin’s discovery marked one of the most dramatic turning points in medical history. In the early 1920s, when diabetes was essentially a death sentence, Frederick Banting and his colleagues at the University of Toronto demonstrated for the first time that a pancreatic extract could be used to treat patients with type 1 diabetes. The initial breakthrough occurred in 1921–1922, when crude animal pancreatic extracts were first administered to patients, resulting in immediate and life‐saving improvement in glycemic control. This milestone quickly led to the first successful treatment of a 14‐year‐old patient in January 1922, initiating a cascade of clinical applications that reshaped the field of endocrinology. Soon after the discovery, the Toronto group refined their extraction methods and purified insulin from animal pancreata. The rapid bench-to-bedside translation of these experiments was remarkable, and within a year large-scale production was undertaken. Insulin soon became available on a commercial scale, and its discovery earned immediate international recognition as a true “miracle drug.”

The early use of insulin was characterized by challenges in terms of purity and potency. The initial preparations contained impurities that sometimes caused adverse reactions and allergic responses, but they nonetheless saved lives. Early Nobel Prizes (for example, Macleod and Banting received theirs in 1923) underscored both the scientific and clinical significance of these initial findings. Over the following decades, researchers and clinicians gradually improved extraction and purification protocols. These improvements enabled the transition from crude, animal‐derived pancreatic extracts to more refined preparations that were not only safer but could also be dosed more accurately. These breakthroughs set the stage for insulin’s central role in diabetes management.

Insulin's Role in Diabetes Management
From its inception in the early 1920s, insulin quickly became recognized as the cornerstone of therapy for type 1 diabetes and later extended to treat advanced cases of type 2 diabetes. Its ability to replace the missing pancreatic hormone transformed diabetes from a rapidly fatal disease to a manageable chronic condition that allowed patients to live longer, with an improved quality of life. Early on, insulin’s success also revolutionized the scientific study of protein chemistry, as it was one of the first proteins to be purified, sequenced, and later, structurally characterized using techniques such as X‐ray crystallography.

Clinically, insulin evolved into a tool for mimicking the body’s diurnal insulin secretion. Initially administered in multiple daily injections based on blood glucose monitoring, it was refined into regimens that aimed to both replace basal (background) and prandial (mealtime) insulin needs. Over time, the therapy has been enhanced by combining insulin injections with evolving technologies such as continuous glucose monitoring and insulin pumps. These developments accentuate the link between optimal glycemic control and the reduction of both acute complications (like hypoglycemia) as well as long‐term microvascular and macrovascular sequelae. The dual impact—improving not only the life expectancy but also the metabolic control—continues to be a driver for ongoing research.

Regulatory Approval History

Initial Approval and Key Milestones
The regulatory approval history of insulin spans nearly a century and illustrates a trajectory from basic biological discovery to a well‐regulated clinical treatment. In the early days following its discovery, insulin was quickly adopted into clinical practice without the modern systematic regulatory pathways we have today. During the 1920s, insulin’s use was largely driven by clinical necessity and the urgency of saving lives, and although formal approval systems were not in place then, the overwhelming clinical benefit quickly made insulin the standard of care.

Within the United States and many other countries, following the initial distribution of animal-derived preparations, regulatory authorities later developed guidelines to ensure the purity, potency, and safety of pharmaceutical products. As technology improved, the first pure formulations of insulin—a milestone in biotechnology—were recognized as breakthroughs. For instance, purified formulations reduced the frequency of adverse immunologic responses and paved the way for dosing standardization. In subsequent decades, improvements in manufacturing were validated by clinical trial data, and regulatory bodies such as the FDA began formally approving insulin preparations once robust data supported their safety and efficacy.

A significant milestone came with the advent of recombinant DNA technology in the 1980s. Recombinant human insulin was introduced as a safer and purer alternative to animal insulin. This technology not only offered an unlimited supply but also reduced immunogenicity and variability between batches. The evolution of insulin preparations into human and then insulin analogs has been overseen by regulatory agencies through extensive clinical trial data submissions, postmarketing surveillance, and ongoing quality control standards.

One prominent example of regulatory evolution is the advancement of alternative delivery systems. In 2006, the U.S. FDA approved inhaled insulin (Exubera) which was initially hailed as the “holy grail” for non-invasive insulin delivery. However, despite initial enthusiasm driven by the hope for needle-free administration, the product was withdrawn a year later because of low bioavailability (approximately 10%), unpredictable absorption patterns, and commercially poor uptake. This case underscored the regulatory challenges in balancing patient convenience with clinical efficacy and safety measures.

Later on, biosimilar insulins began to emerge as patents for leading insulin products expired. For example, the approval of Semglee as the first interchangeable insulin biosimilar by the FDA represented a revolutionary step in simplifying the pathway for other investigational biosimilar products in the insulin market. Through the regulatory pathway designed for biosimilars, the FDA demonstrated that it was possible to ensure high levels of similarity in both pharmacokinetic and pharmacodynamic profiles while providing potentially lower-cost alternatives for patients. In addition to these product-specific milestones, detailed regulatory guidelines have evolved concerning device compatibility—as seen with the approval of new-generation insulin pumps such as Medtronic’s MiniMed 780G, which now incorporates advanced continuous glucose monitoring technology and automated meal detection algorithms.

Changes in Formulations and Delivery Methods
Over the decades since its discovery, insulin formulations have undergone significant changes. Early formulations were crude extracts from animal pancreata with short durations of action and significant variability in potency. As processing techniques improved, intermediate-acting insulins and long-acting insulins were introduced to approximate the natural basal secretion patterns. Innovations such as Neutral Protamine Hagedorn (NPH) insulin were milestones in the quest for a basal insulin replacement, offering prolonged action with fewer injections.

In later years, the introduction of insulin analogs represented a major advance. Rapid-acting analogs such as insulin lispro (approved in 1996) and later short-acting analogs provided improved postprandial control by acting more quickly than conventional human insulin. Likewise, long-acting analogs such as insulin glargine (approved in 2000) and insulin detemir were created to provide a constant low level of insulin over 24 hours or even longer. Each of these products underwent rigorous clinical trials and regulatory review processes that assessed not only glycemic efficacy but also the risks of hypoglycemia and other adverse effects.

Moreover, the delivery methods for insulin have evolved from syringes and vials to insulin pens and pump systems which improve dosing accuracy and patient compliance. The regulatory approvals extended to these devices as well, and clinical studies have compared the benefits of continuous subcutaneous insulin infusions (CSII) with multiple daily injections (MDI), showing advantages in both glycemic outcomes and quality of life for patients. The integration of advanced insulin delivery systems such as closed-loop “artificial pancreas” systems has further transformed the therapeutic landscape, requiring a multifaceted review process that combines device and drug evaluations under regulatory guidelines.

Thus, the regulatory history has been tightly interwoven with technological innovation. Each new formulation or device has required substantial clinical evidence showing improvements in pharmacokinetics/dynamics, patient safety, and practical outcomes—often provided through multicenter clinical trials and post-marketing surveillance, thereby ensuring both regulatory compliance and real-world effectiveness.

Clinical Development Pathway

Early Clinical Trials
The clinical development of insulin began with a rapid translation of early animal experiments into human trials in the early 1920s. The pioneering studies demonstrated dramatic improvements in blood glucose control and reduction of ketonuria in diabetic patients—this early phase was essentially proof-of-concept and life-saving evidence. Early dose titration and individualized treatment regimens were developed at a time when standard clinical trial design had not yet evolved. Physicians observed the immediate metabolic effects—such as rapid reductions in glycosuria—and quickly recognized that insulin therapy would need continuous refinement to match physiologic needs.

During those formative years, patients were titrated on the basis of clinical observations rather than strictly defined biochemical endpoints. The major outcome from these early trials was survival. Subsequent retrospective analyses and observational studies cemented the idea that insulin therapy not only lowered blood glucose levels dramatically but also reduced short-term mortality. Although the early clinical trials were modest in scale by today’s standards, they laid the essential groundwork for the later, more tightly controlled, randomized controlled trials (RCTs). They validated insulin’s immediate therapeutic benefit and provided the impetus for intensive research and further development.

As the scientific understanding of diabetes evolved, so did the design of clinical studies involving insulin. With the improvement in biochemical assays (such as radioimmunoassays for insulin measurement) and later pharmacodynamic endpoints, early trials gradually incorporated more rigorous control groups, greater numbers of patients, and longer follow-up periods. This progression allowed researchers to begin comparing different insulin regimens, exploring the differences between rapid-acting, intermediate-acting, and long-acting formulations in both type 1 and type 2 diabetes settings. In addition, early clinical studies also assessed adverse events, particularly the risk of hypoglycemia, which—in turn—influenced later dosing strategies and formulation modifications.

Advances in Clinical Research
The clinical research on insulin has undergone several transformative phases over the past century. With the introduction of recombinant DNA technology in the 1980s, human insulin replaced the animal-derived formulations, and numerous RCTs were conducted that compared the glycemic control, immunogenicity, and long-term safety of recombinant human insulin against older preparations. These studies demonstrated that recombinant human insulin was effective in controlling blood glucose with a significantly reduced risk of allergic reactions and batch variability.

By the late 1980s and into the 1990s, insulin analogs entered clinical research. Early clinical trials with rapid-acting analogs (such as insulin lispro, approved in 1996) and long-acting analogs (such as insulin glargine, approved in 2000) were designed to more closely mimic physiological insulin secretion. These trials compared postprandial glucose excursions, overall glycemic variability, risk of hypoglycemia, and patient-reported outcomes. Longer, multicenter trials such as those conducted by Joslin and other leading diabetes researchers compared basal-bolus regimens to conventional sliding scale protocols. These studies provided strong evidence that carefully titrated and physiologically matched insulin delivery could reduce both acute complications (hypoglycemia) and long-term complications such as microvascular damage.

During the 2000s, as the regulatory framework became more stringent and the market more competitive, further clinical development was aimed at refining both insulin formulations and delivery systems. For example, studies of continuous subcutaneous insulin infusion (CSII) vs. multiple daily injections (MDI) emerged and were published in high-impact journals, comparing outcomes like HbA1c levels, the incidence of severe hypoglycemia, and overall quality of life improvements. In addition, the integrated development of insulin delivery devices, including insulin pens, pumps, and now closed-loop systems, was supported by robust clinical trials that evaluated not only glycemic outcomes but also user convenience and adherence metrics.

One of the more striking developments was the clinical testing of alternative delivery routes. As noted earlier, inhaled insulin was approved in 2006 following phase II/III studies demonstrating a rapid absorption profile that closely mimicked the postprandial insulin surge. Although this product was later withdrawn because of issues with bioavailability and absorption variability, the clinical development pathway for non-invasive insulin delivery continues. New clinical trials testing technologies such as oral insulin nanoparticles, buccal delivery systems, and transdermal patches are typically preceded by extensive preclinical work and pilot clinical studies that assess pharmacokinetics and pharmacodynamics in healthy volunteers before moving to patient populations.

Clinical research during these phases has not only focused on improving glycemic control but also on reducing the burden of therapy. Large-scale outcome studies, such as those evaluating intensive insulin protocols in type 2 diabetes (e.g., the 4-T trial), have helped to refine treatment algorithms and to illuminate the relationship between early insulin initiation, glycemic control, and long-term complications. The advances in continuous glucose monitoring (CGM) and improvements in data connectivity have also enriched clinical development by enabling real-time assessments of insulin efficacy and safety in outpatient settings. These studies have continually reaffirmed that improved technology combined with physiological insulin analogs translates to better metabolic outcomes and fewer treatment-related adverse events.

Current and Future Directions

Innovations in Insulin Therapy
Today, the treatment landscape for diabetes is once again evolving, and innovative insulin therapies are quickly becoming a reality. In current clinical practice, insulin therapy has moved beyond simple basal and prandial replacement, incorporating advanced delivery systems, combination therapies, and precision dosing algorithms. One of the most promising directions comes from the development of “smart” (or glucose-responsive) insulins, which are engineered to change their activity depending on the blood glucose level. Such innovations have the potential to dramatically reduce the risk of hypoglycemia by automatically modulating insulin’s bioavailability in response to the patient’s glycemic state.

Alongside molecular innovations, the development of digital technologies has fostered the creation of closed-loop insulin delivery systems or “artificial pancreas” platforms. These systems combine continuous glucose monitoring with insulin pumps that automatically adjust dosing based on sophisticated algorithms, thereby mimicking the endogenous insulin secretion pattern with minimal user intervention. Clinical trials in recent years have validated the safety and efficacy of these automated systems, and regulatory approvals have steadily increased their uptake in various populations (from children to adults).

Another area of rigorous research is the field of insulin analogs with ultra-long or ultra-rapid action profiles. Ultra-long-acting insulins such as degludec extend the duration of action beyond 24 hours, allowing for once-daily or even less frequent dosing. On the other hand, ultra-rapid-acting analogs are designed to more closely match the postprandial insulin surge, thereby improving mealtime glucose control while reducing postprandial hypoglycemia. These innovations result from decades of research into insulin’s three-dimensional structure, receptor binding characteristics, and aggregation properties. Studies using structure-guided design have resulted in analogs with specific amino acid substitutions and side-chain modifications that alter absorption kinetics and stability—a journey that began with the early achievements of Sanger and Hodgkin.

In parallel, the development of biosimilar insulins is transforming market dynamics and improving accessibility. Biosimilar products, such as Semglee, have gained regulatory approval as interchangeable alternatives to established insulin analogs, reducing costs while maintaining high standards of efficacy and safety. Clinical studies have demonstrated that these biosimilars have comparable pharmacokinetics and pharmacodynamics to their reference products, and regulatory agencies use a “totality-of-the-evidence” approach to ensure that only highly similar products are approved.

Moreover, researchers are actively exploring novel non-invasive methods of insulin delivery. While subcutaneous injections remain the mainstay, alternative routes—such as inhaled, oral, nasal, buccal, and transdermal systems—continue to be the focus of preclinical and early-phase clinical studies. Although the initial experience with inhaled insulin (Exubera) was not sustained commercially, it provided valuable lessons that have spurred the ongoing development of second-generation formulations that seek to overcome previous limitations such as low bioavailability and variable absorption. In addition, nano-encapsulation technologies and carrier systems are under investigation to protect insulin from enzymatic degradation in the gastrointestinal tract, in hopes of eventually achieving effective oral insulin delivery.

Flexible dosing and combination therapies are additional areas of innovation. Several studies have emerged to compare multiple insulin regimens—including basal-bolus, premixed formulations, and continuous subcutaneous infusion—with attention to not only metabolic outcomes (HbA1c, glycemic variability) but also quality of life measures and patient satisfaction. Newer insulin pens and patch pumps have been designed to reduce injection pain, improve dosing accuracy, and minimize patient burden. Finally, next-generation systems integrate patient data digitally to adjust dosing in real-time, using complex algorithms that consider recent insulin on board, carbohydrate intake, and blood glucose trends.

Future Research and Development
Looking to the next century, a number of promising research directions are emerging that hold the potential to further revolutionize insulin therapy. Foremost among these is the further optimization of “smart” insulins that are glucose-responsive, which could allow insulin to be released only when the blood sugar exceeds certain thresholds. Such a system would dramatically improve the safety profile of insulin therapy by reducing the incidence of hypoglycemic episodes, a goal that has been elusive with current open-loop systems.

Future clinical trials are expected to focus extensively on long-term outcomes and on patient-centered parameters, such as quality of life and treatment satisfaction. With the increasing integration of wearable technology and digital health platforms, real-time data capture may soon allow for more adaptive clinical trial designs, where insulin therapies are continuously refined based on individual patient data. This personalized approach to treatment not only promises to improve glycemic control but also to enhance adherence by tailoring therapy to each patient’s lifestyle and metabolic needs.

The future clinical development pathway is likely to emphasize the continued evaluation of biosimilar insulins as regulatory authorities worldwide adopt standardized criteria for similarity comparisons. This will drive greater market competition, improved affordability, and increased accessibility for patients across the globe. Furthermore, coordinated global research efforts addressing the current hurdles of non-invasive delivery—especially achieving high and reproducible bioavailability—will benefit from collaborations between academia, industry, and governmental agencies. Multi-center studies and multinational clinical trials are anticipated to play a critical role in these future developments.

Research into novel insulin gene editing techniques and cell-based therapies also shines as a potential future frontier. Scientists are investigating ways to regenerate insulin-producing beta cells from stem cells, thereby reducing or even eliminating the need for exogenous insulin. Preliminary studies in animal models have shown encouraging results, and early human trials may emerge in the coming years to test the safety and efficacy of such regenerative approaches. While these strategies are still in relatively early stages, they underscore the transformative potential of combining molecular biology and clinical medicine in the fight against diabetes.

Another growth area is the use of artificial intelligence (AI) and machine learning algorithms to refine insulin dosing and management strategies. With large datasets from continuous glucose monitors and insulin pumps now available, AI-based systems are being developed to predict glycemic patterns and recommend adjustments in therapy. This digital revolution, coupled with improved telemedicine platforms, might soon enable remote monitoring and personalized adjustments for insulin therapy that were unimaginable just a decade ago.

Finally, future research will address the broader systemic issues in diabetes care. Although insulin therapy itself is highly effective, delays in initiation (often observed in general practice) continue to hamper optimal glycemic management. Research focusing on understanding the barriers to insulin initiation—including psychosocial factors and clinician inertia—will further inform interventions that promote earlier and more effective use of insulin. Recent studies have underlined the importance of patient education, the role of nurse educators, and the benefit of integrated care models in overcoming resistance to insulin therapy. Moreover, regulatory and reimbursement policies will also continue to evolve, potentially paving the way for innovations to be made available to a wider patient population across different socioeconomic contexts.

Conclusion
In summary, the approval history and clinical development pathway of insulin illustrate a remarkable trajectory—from the early, life-saving trials in the early 1920s to the multi-faceted, regulated, advanced science of the 21st century. Initially discovered by Banting and Best in 1921–1922, insulin’s early clinical development was driven by urgent needs that transformed diabetes from a fatal illness to a manageable chronic disease. Insulin’s evolution in formulation—from crude animal extracts to purified formulations, then recombinant human insulin and insulin analogs—has been paralleled by regulatory milestones that ensured more reliable, safe, and tailored therapy. Regulatory agencies have, over time, increasingly emphasized quality, consistency, and patient safety, as seen in the approvals of recombinant human insulins, innovative formulations like inhaled insulin (despite its setbacks), and biosimilar products like Semglee.

Clinically, early trials were rudimentary by modern standards yet demonstrated the life-saving capability of insulin. Over the decades, clinical research has advanced to include rigorously designed RCTs, multicenter studies, and outcome analyses that have refined dosing, improved patient safety (especially by reducing hypoglycemia), and advanced the integration of delivering devices—from syringes to insulin pens and sophisticated closed-loop systems. The clinical development pathway now incorporates not only the evaluation of glycemic outcomes but also patient-reported quality of life, cost considerations, and long-term safety over decades of therapy.

Currently, innovations in insulin therapy are focusing on “smart” insulins, non-invasive delivery routes (oral, nasal, transdermal), and highly integrated digital health systems that enable real-time adjustments in therapy—all of which promise to further improve patient outcomes while reducing the burden of daily injections. Future research will undoubtedly address the challenges of improving bioavailability in non-invasive systems, harnessing AI for personalized dosing, and even exploring regenerative approaches that could eventually minimize or replace the need for exogenous insulin.

In conclusion, from the early 20th century discovery to the modern era of digitalized, highly personalized therapy, insulin’s development pathway exemplifies a general-to-specific-to-general continuum. Initially, insulin revolutionized the treatment of diabetes with life-saving interventions on a broad scale; subsequent innovations allowed clinicians to achieve more precise, individualized glycemic management; and future directions point toward even more revolutionary methods that promise to transform insulin therapy once again. The journey of insulin, molded by scientific ingenuity, rigorous clinical research, and evolving regulatory frameworks, remains central to the treatment paradigm in diabetes and provides a testimony to the power of translational medicine.