The development and regulatory approval of pharmaceuticals represents one of the most rigorous scientific and administrative processes in modern healthcare. This comprehensive analysis explores the

(1) historical evolution of pharmaceutical regulation in the United States
(2) the establishment of the Food and Drug Administration (FDA)
(3) provides a detailed examination of each stage in the current drug approval process.

Understanding this complex journey from laboratory to the pharmacy shelf provides insight into the delicate balance between ensuring public safety, efficacy and fostering pharmaceutical innovation.

HISTORICAL CONTEXT – FROM UNREGULATED REMEDIES TO SCIENTIFIC REGULATION

The history of pharmaceutical development spans centuries, evolving from rudimentary practices to the sophisticated scientific endeavor recognized today. Early drug development in Europe rested with the people who tanned hides or performed apothecary work. The people who tanned hides, tasted their “chemicals” for use to treat malady’s but sometimes they died due to toxicity.

By the mid-19th century, a more structured approach to pharmaceuticals emerged with companies such as Merck, GlaxoSmithKline, Pfizer, Eli Lilly, and Squibb, pioneering research-driven drug development. Despite these advancements, unregulated medicines continued to thrive in the market, many of which contained undisclosed or harmful ingredients such as alcohol, cocaine, or opium.

One of the most infamous examples was Lydia Pinkham’s Vegetable Compound, a widely marketed remedy for women’s reproductive health issues that contained high levels of alcohol. In the US, around 1870-80s horse drawn carts would pull into towns advertising Lydia Pinkham Wonderful Elixir. Since the Elixirs were high in alcohol content, they were used to relieve muscular stress, reduce pain, and affect mood.

Such unregulated products posed significant health risks, ultimately leading to public outcry and the demand for regulation. The sulfa antibiotic drug, sulfanilamide, disaster of 1937, which resulted in over 100 deaths due to toxic solvent diethylene glycol, highlighted the need for strict pharmaceutical oversight. In response, the U.S. Congress passed the 1938 Federal Food, Drug, and Cosmetic Act (FD&C Act), which required pharmaceutical companies to demonstrate the safety of their products before marketing.

Further regulatory advancements came with the 1962 Kefauver-Harris Amendments, prompted by the thalidomide tragedy in Europe, which led to severe birth defects. The US FDA did not approve the use of thalidomide, though. These amendments introduced the requirement for both efficacy and safety to be proven before drug approval, marking the introduction of randomized controlled trials as the gold standard in drug testing. Later, the Hatch-Waxman Act of 1984 refined the regulatory process by establishing a streamlined approval pathway for generic drugs while maintaining incentives for pharmaceutical innovation.

EASTABLISHMENT AND EVOLUTION OF THE FDA

The FDA was formally established in 1927 as the Food, Drug, and Insecticide Administration and was later renamed the Food and Drug Administration (FDA) in 1930. Its regulatory authority expanded significantly with the FD&C Act of 1938, which required manufacturers to provide safety data before marketing their drugs. Over time, the FDA introduced additional oversight mechanisms, ensuring that all pharmaceuticals underwent rigorous evaluation.

To address evolving medical needs and scientific advancements, the FDA has implemented expedited approval pathways. These include Fast Track designation, which accelerates the approval of drugs for serious conditions with unmet medical needs, and Breakthrough Therapy designation, which facilitates the development of drugs showing substantial clinical benefit over existing treatments. Accelerated Approval allows drugs to be approved based on surrogate endpoints rather than clinical outcomes, expediting access to life-saving medications. Priority Review shortens the FDA’s standard review period from 12 months to 6 months for drugs deemed essential for urgent medical needs.

With rapid advancements in biotechnology, the FDA now oversees the approval of not only small molecules, but also biologics, gene therapies, and cell-based therapies, adapting its regulatory framework to the expanding landscape of pharmaceutical innovation.



In 2024, MarinBio successfully passed the FDA inspection with no 483s and no observations and passed the EU inspection.

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MODERN DRUG DEVELOPMENT AND APPROVAL PROCESS

Discovery and Preclinical Research

The pharmaceutical development process begins with basic research, where scientists identify disease mechanisms and therapeutic targets. Advances in molecular biology, AI-driven drug discovery, and CRISPR gene editing have accelerated this phase, allowing for the rapid identification of promising compounds. These molecular “targets” within diseases usually are key components of the pathophysiology of the disease process that provides clues for scientists in drug discovery and development. Once the best compound is identified, it undergoes preclinical testing to evaluate its pharmacokinetics (how the drug is absorbed, distributed, metabolized, and excreted), pharmacodynamics (the drug’s mechanism of action and biological effects), and toxicology (potential harmful effects).

These studies, conducted using cell cultures (in vitro) and animal models (in vivo), assess acute and chronic toxicity, genotoxicity, carcinogenicity, and immunogenicity, for small molecules, biologics and gene therapies. These tests lay the foundation for demonstrating the safe, non-toxic application to humans for the proposed medication. These tests are extensive in order to show whether the compound has the potential to cause mutagenic or chromosomal aberrations. Pharmacology and toxicology studies strive to demonstrate that the drug is not toxic at doses scheduled for affecting the molecular target and disease state. In addition, all the chemical or biologic manufacturing data for the experimental therapeutic must be rigorously documented and evaluated. Preclinical research typically takes 1-2 years and must comply with Good Laboratory Practice (GLP) regulations. If successful, the sponsor submits an Investigational New Drug (IND) application to the FDA.

MarinBio offers collaborative contract research, testing, and small-scale biologics manufacturing services, including GMP/GLP-compliant cell-based assays, potency and lot release assays, flow cytometry, and protein services. We specialize in assay development and validation, supporting drug development processes from concept to FDA approval. With over 30 years of experience, MarinBio provides expertise in gene therapy assays, immunotherapy testing, and cellular immunoassays.

Investigational New Drug (IND) Application for Human Clinical Studies

An IND application includes preclinical data on pharmacology, toxicology, and chemistry, as well as detailed information about the manufacturing process and clinical trial protocols. The application also contains scientific and clinical rationale including strategies for protection of human volunteers and a clinical plan for testing. The FDA may review the IND within 30 days, assessing whether the drug is safe for human testing. If no concerns arise, the sponsor may proceed with clinical trials in human subjects.

There are three types of INDs:

  • Investigator: An Investigator IND is submitted by a physician who both initiates and conducts an investigation.
  • Emergency Use: The IND allows the FDA to authorize use of an experimental drug in an emergency situation.
  • Compassionate Use: Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions [3].

Once the IND is submitted, the sponsor must wait at least 30 calendar days before initiating any clinical trials. During this time, the FDA reviews the application to ensure that study participants will not be exposed to unreasonable risks [3]. If the FDA does not object within this timeframe, clinical trials may proceed.

Clinical Development (Phase 1–3 Trials)

Figure 1 illustrates the stages of clinical development from Phase I to FDA approval and post-marketing

 

The stages of clinical development from FDA Approval Stages for Pharmaceuticals. Phase I to FDA approval and post-marketing.

Fig. 1 Schematic representation of clinical development from Phase I to FDA approval.

 

Phase 1: First-In-Human Safety Studies

Phase 1 clinical trials represent the first stage of human testing, primarily focusing on safety, tolerability, and pharmacokinetics. These trials typically involve 20-100 participants, often healthy volunteers or, in cases of severe diseases like cancer, patients with the medical condition. The experimental compound is given by the intended route of administration oral (tablets, capsules, liquids) parenteral injections (e.g. intravenous, subcutaneous, intramuscular, or others), topical, inhalation, etc. These studies are conducted over 1 to 2 years.

Phase 1 trials focus on determining a safe dosage, drug absorption, and duration of activity in the body. Researchers use a dose-escalation approach, gradually increasing doses to identify the maximum tolerated dose and any dose-limiting toxicities. Women of childbearing age are often excluded for safety reasons. In cases of severe or life-threatening diseases like cancer, patients rather than healthy volunteers may participate due to the ethical balance of risk and potential benefit. Approximately 70% of investigational drugs advancing to the next phase.

Phase 2: Efficacy and Dose Optimization

Phase 2 trials evaluate the drug’s effectiveness and determine optimal dosing while continuing to monitor safety. Conducted in 100-300 patients, these trials often employ randomized controlled trial designs and pharmacodynamic studies to refine treatment strategies.

Phase 2 trials are a crucial stage in drug development. The objectives in Phase 2 are determining the optimal effective dose using the method of delivery or route of administration, dosing schedule or interval and duration of application and continuing to monitor the product safety as patients receive careful, continuous assessments. Researchers assess both primary and secondary efficacy endpoints. Lasting 1 to 3 years, this phase has the lowest success rate, with approximately 30-35% of drugs progressing to Phase 3, as many fail due to insufficient efficacy, safety concerns, or intolerable side effects.

Phase 3: Large-Scale Confirmatory Trials

Phase 3 trials are to confirm and extend previous findings from Phase 2 in an expanded population of patients. The trials confirm a drug’s long-term safety, efficacy, and dosage in a more diverse population of 1,000-3,000+ patients. What remains important throughout the studies are monitoring further safety, effectiveness and absolute best dosage. These trials are conducted across multiple sites, often globally, and utilize randomized, placebo-controlled designs. Taking 2-5 years to complete, Phase 3 trials are critical for identifying rare side effects and ensuring that the drug provides a significant clinical benefit. Despite reaching this stage, approximately 60% of drugs are successful in Phase 3.

MarinBio supports Phase I, II, and III clinical trials by offering GLP-compliant assay development, qualification and validation services to ensure precise and reliable data throughout the drug development process. Our expertise in bioanalytical services includes pharmacokinetic (PK) and pharmacodynamic (PD) assays, enabling the assessment of drug behavior, dosing, efficacy, and safety across preclinical and clinical settings. Additionally, we provide sample analysis, lot release testing, and stability studies, adhering to FDA and ICH guidelines to maintain the highest quality standards for regulatory compliance.

NEW DRUG APPLICATION (NDA) OR BIOLOGICS LICENSE APPLICATION (BLA)

If a drug successfully completes Phase 3 clinical trials, the developer submits either a New Drug Application (NDA) for small molecules and peptides or a Biologics License Application (BLA) for antibodies, recombinant proteins, vaccines, and other biological products. These applications serve as comprehensive dossiers containing all data gathered throughout the drug’s development, including results from preclinical and clinical testing, detailed information on the drug’s composition and manufacturing processes, proposed labeling and prescribing information, patent details, and any international marketing history.

The FDA reviews NDAs and BLAs through specialized divisions: the Center for Drug Evaluation and Research (CDER) evaluates NDAs, while the Center for Biologics Evaluation and Research (CBER) assesses BLAs. The review process, conducted by teams of experts including physicians, statisticians, chemists, and pharmacologists, typically takes 12 months, though priority reviews for drugs addressing urgent medical needs may be completed within six months. Additionally, the FDA may consult advisory committees composed of external experts to provide independent recommendations.

At the conclusion of the review, the FDA issues one of three decisions. An Approval allows the drug to be marketed. A Complete Response Letter (CRL) indicates that the application cannot be approved in its current form, with specific deficiencies and recommendations for improvement. A Not Approvable decision signifies that the drug is rejected due to serious safety or efficacy concerns. The cumulative probability of a drug moving from Phase I through Phase 3 of FDA approval is less than 1.0% (Data from 2011-2020; ClinicalDevelopmentSuccessRates2011_2020.pdf)

Phase 4: Post-Marketing Surveillance

FDA approval does not signify the end of a drug’s evaluation process. Phase 4, or post-marketing surveillance, begins once a drug enters the marketplace and continues throughout its commercial life. This phase plays a vital role in identifying rare or long-term side effects that may not have been evident during controlled clinical trials. It also helps monitor the drug’s performance in broader populations, including those who may have been underrepresented in earlier studies. Additionally, Phase 4 evaluates the drug’s real-world effectiveness compared to its performance in controlled trial settings and assesses how it compares with other treatments introduced since its approval. Another key aspect of this phase is identifying potential new therapeutic uses or indications.

In some cases, the FDA mandates post-marketing requirements (PMRs) as a condition of approval to address specific safety concerns or unresolved questions from earlier studies. Data collected during Phase 4 can lead to modifications in the drug’s labeling, the addition of new warnings, or, in rare instances, its withdrawal from the market if significant safety risks emerge. This ongoing monitoring ensures that the benefits of a drug continue to outweigh any potential risks, reinforcing the FDA’s commitment to public health and safety.

MarinBio supports post-marketing surveillance by offering stability monitoring and GMP-compliant lot release assays, ensuring long-term consistency and regulatory compliance of pharmaceutical products. Their cell-based assays are designed to be accurate, robust, and reflective of in vivo conditions, making them suitable for post-market monitoring. Additionally, MarinBio provides comprehensive bioanalytical services, including immunoassays and flow cytometry, to monitor drug safety and efficacy in real-world settings.

IMPACT AND SIGNIFICANCE OF THE FDA APPROVAL PROCESS

The FDA’s rigorous drug approval process has significantly improved public health and drug safety. However, this process remains time-consuming and costly, with an average cost of $2.6 billion and 10-15 years required to bring a new drug to market. Challenges include high failure rates, complex regulatory compliance, and emerging technologies like gene therapy and personalized medicine.

CONCLUSION

The evolution of pharmaceutical regulation in the United States reflects a continuous effort to balance public safety with access to innovative treatments. From the unregulated patent medicines of the 19th century to today’s rigorous multi-phase approval process, regulatory advancements have been shaped by scientific progress, public health crises, and legislative interventions. The modern FDA approval framework, while adding time and cost to drug development, plays a crucial role in preventing unsafe or ineffective products from reaching the market. As scientific understanding and medical technologies continue to advance, the regulatory landscape must adapt to accommodate emerging therapies while maintaining stringent safety and efficacy standards.

Looking ahead, the challenges of regulating complex treatments such as cell and gene therapies, personalized medicines, and digital therapeutics will likely drive further refinements in the approval process. Despite these advancements, the core principles of demonstrating safety and efficacy before market entry remain as essential today as they were in the early 20th century. The FDA’s comprehensive regulatory framework not only safeguards public health but also serves as a global benchmark for pharmaceutical approval, influencing international regulatory policies and ensuring that patients receive thoroughly evaluated and reliable medications.

Partner with MarinBio for Expert Bioanalytical Support

With over 30 years of experience, MarinBio’s expert scientists provide comprehensive assay development, qualification, and validation to support your drug development journey. Our team specializes in stability testing, clinical sample analysis, and lot release assays, ensuring the highest standards of regulatory compliance. We have successfully represented clients to the FDA, helping to navigate complex regulatory challenges with confidence. MarinBio has successfully passed FDA and EU (EMA) audits.

Let MarinBio be your trusted partner in advancing your therapeutic programs. Contact us today at info@marinbio.com or call 415-883-8000 to discuss how we can accelerate your success. Visit www.marinbio.com to learn more about our specialized services. Your breakthrough deserves the best—partner, and with MarinBio you can move forward with confidence!

 

About Marin Biologic Laboratories

Our Recent Publication/Meeting Presentation on Gene Therapy

American Society of Hematology (ASH) Annual Meeting 2024.

Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

Comprehensive Assay Solutions for In Vitro and Cell Based Potency Assays and Pharmacokinetics Studies- Our Expertise

With 30 years of expertise in cell culture, cell-based assays, and preclinical/clinical PK/PD analysis, we specialize in offering assay services essential for a wide variety of therapeutic drug development programs, preclinical studies, IND/BLA applications, and commercialization. Our comprehensive services include both preclinical non-GLP and GLP assays, as well as non-GMP and GMP assays, providing critical support throughout the entire development pipeline.

Watch the following video and explore our latest presentation on the development and validation of potency and pharmacokinetic (PK) assays for AAV vectors, highlighting innovative methodologies and industry-leading expertise.

 

 

Download the full presentation: Development of Custom Cell Based and In vitro Potency and Pharmacokinetics (PK) Assays for AAV vectors- Marin biologic Laboratories

 

Development of Cell-Based Potency Assays: Case Studies and Blogs from Marin Biologic Laboratories (MarinBio)

 

Drug Discovery & Development Assays Offered by Marin Biologic Laboratories (MarinBio)