• Comprehensive Breakdown of FDA Approval Stages for Pharmaceuticals

    MarinBio's Blog

    Posted on May 12, 2020


    Early drug development in Europe rested with the people who tanned hides. They tasted their chemicals and sometimes treated malady’s and sometimes died due to toxicity. In Europe in the mid-1800s Merk, GlaxoSmithKline (Germany), Pfizer, Eli Lilly and Squibb (US) were starting a scientific approach to pharmaceuticals. There was also the non-scientific pharmaceutical development.  In the US, around 1870-80s horse drawn carts would pull into towns advertising Lydia Pinkham Wonderful Elixer, for women and their problems. Since the Elixer’s were high in drinking alcohol content, they were wonderful to relieves muscular stress, reduces pain, and can affect mood.

    Moving to the 1900s, due to a mass poisoning calamity of over hundred patients caused by the elixir of the sulfa antibiotic drug sulfanilamide in 1937, the U.S. Congress passed the Federal Food, Drug and Cosmetic Act in 1938.  This marked the birth of the Food and Drug Administration (FDA).  This law initiated the regulatory environment overseeing all aspects in the evaluation of new drugs and their safe development to approval and eventual marketplace including dispensing of drugs.  It required that a drug manufacturer prove the safety of a drug before it could be marketed, authorized inspection of factories, and established penalties for fraudulent claims and misleading labels.


    The discovery and development of a new drug, whether it is a new chemical entity (NEC or small molecules) or new molecular entity (NME or biologics, antibodies, recombinant human proteins, gene constructs) or a cell based therapy for particular therapeutic indications or diseases is generally divided into phases.


    The first step is the basic research or preclinical phase where scientists study diseases gaining understanding and identifying targets within various biochemical pathways prominent in disease manifestation.  Through pharmacology, chemistry, molecular biology, systems biology and computer science techniques, scientists try to find a promising chemical or biologic experimental therapeutic that could alleviate symptoms or cure the disease.  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.  All of this work combines a variety of investigative laboratory research approaches and disciplines using cells (in vitro) to animal studies (in vivo).  The purpose of these preclinical studies is to assess the biological activity of potential molecules on targets and disease models.

    MarinBio is expert at in vitro models in our cell based assays of various diseases and works with clients to devise experiments to investigate Mechanism of Action (MOA) or screening drug candidates.

    The next step before attempting to test in humans, is to study the safety, tolerability and dose, general toxicology, of the potential drug in living animals usually rodents (mice and rats).  The FDA requires certain animal tests to be performed before humans are exposed to an NCE or NME.  These tests lay the foundation for demonstrating the safe, non-toxic application to humans for the proposed medication.  These tests are extensive showing if the compound has the potential to cause mutagenic or chromosomal aberrations, in pharmacology and toxicology studies demonstrating the drug is not toxic at certain doses that would most likely be effective in affecting the molecular target and disease state.  In addition, all the chemical or biologic manufacturing data for the experimental therapeutic must be rigorously known and evaluated.  This preclinical phase can take 1-2 years to complete.

    MarinBio develops, validates and performs ELISA assays under GLP-GMP Assay Requirements for Pharmacokinetic (PK), Anti-Drug Antibody (ADA) and Neutralizing Antibody Assays to aid drug distribution, toxicity and immunogenicity studies.


    All these scientific specialties, pharmacology, toxicology and chemistry and manufacturing controls make up the bulk of the Investigative New Drug Application or IND that is filed with the FDA for review.  The application also contains scientific and clinical rationale including strategies for protection of human volunteers and a clinical plan for testing.  If the FDA is satisfied with every aspect of documentation which is reviewed by specialty experts within the regulatory agency, the sponsor or company filing the IND will be allowed to proceed to the next phase of drug development, Phase 1 clinical trials or human clinical testing.

    MarinBio is unique in developing lot release potency bioassays as part of our cell based assays to confirm that manufactured lots are similar and thus toxicity studies during preclinical pharmacology can be predictive for designing dosage regimes for the clinic.


    The primary focus of Phase 1 clinical trials, also referred to as first-in-human trials, is the safety, tolerability and pharmacology of a new compound usually involving 20-100 subjects.  This is the stage where small, safe doses of the compound, determined by animal toxicology studies, are gradually increased.  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., to groups of healthy volunteers, who are closely  monitored and supervised by medical personnel.  In disease states that are severe or life-threatening such as cancer, volunteers already afflicted with the disease may be used in Phase 1 clinical trials.  The data collected and analyzed from Phase 1 centers around pharmacokinetics, absorption, tissue distribution and elimination of the drug and importantly, safety considerations or the observance of any toxic side effects.  Phase 1 can take 1-2 years to complete and generally 70% of INDs filed graduate to the next phase of development.

    MarinBio performs many PK, ADA and Pharmaco Dynamic assay (PD, effects of drugs on various pharmacologic parameters) for our clients. For cell based therapeutics, our clients may want to test no effect or modulation in our cell based immunoassays. For gene therapy drugs, we perform transfections and other molecular biology services.


    The next phase in the sequence of drug development is Phase 2 clinical trial which examines effectiveness or efficacy of an NCE or NME.  Phase 2 typically involves 100-300 patients who are suffering in the disease condition the experimental drug is intended to treat.  The objectives collected 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 to continue monitoring the product safety as patients receive careful continuous assessments. Phase 2 can take another 1-2 years to complete.  Many industry outsiders fail to realize that a substantial number of Phase 2 clinical trials are discontinued due to poor NCE or NME effectiveness, safety issues or intolerable side effects.  Only 30-35% of INDs filed with the FDA advance to Phase 3 clinical development.


    Phase 3 clinical trials usually occurs in 1,000-3,000 patients or more (depending on the therapeutic indication) patient volunteers and are the final step before seeking FDA approval.  The objective during Phase 3 is to confirm and extend previous findings from Phase 2 in an expanded population of patients.  These studies can take 2-5 years to complete across numerous clinical sites including international participation.  What remains important throughout the studies are monitoring further safety, effectiveness and absolute best dosage.  Phase 3 studies are expensive, extensive and even though experimental compounds can make it to this phase of clinical development, statistically 10% fail in this phase.  Just because medications make it to Phase 3, it does not guarantee success or approval.  If the drug survives this phase of clinical trials, a New Drug Application (NDA, for small molecules or peptides) or Biological Licensing Application (BLA for antibodies, recombinant human proteins, plasmids, vaccines etc.) is submitted to the FDA.  Different divisions within the FDA review these applications.  CDER (Center for Drug Evaluation and Research) reviews NDAs and CBER (Center for Biologics Evaluation and Research) reviews BLAs, although in certain cases both divisions can weigh-in on reviewing the application dossiers.  These applications are extensive containing information obtained during all the preclinical and clinical testing obtained in the years collected.  Every aspect of drug development is scrutinized:  chemical or biologic makeup including manufacturing process, pharmacology and toxicology of the drugs, human pharmacokinetics, results of every phase of the clinical trials and the proposed usage or labeling.  Upon receiving an NDA or BLA the FDA completes an independent review and makes recommendation whether or not to approve the drug for the therapeutic indication it is intended to treat.  This process usually takes 12 months to review although priority applications could take as little as 6 months.  It is during this process where the drug might be approved or rejected.


    Once a drug is approved it can be marketed.  In certain instances, the FDA can approve a drug but stipulates conditions that must be met after the drug is marketed.  This commercialization requirement is referred to as Phase 4. MarinBio supports clients for safety bioassays for manufacturing post-marketing.

    THIS IS WHAT MARINBIO CAN DO:  MarinBio scientists have over 25 years of experience helping our clients to develop, qualify and validate assays as well as assaying stability samples, testing clinical samples and performing manufactured lot release assays. We have successfully represented our clients to FDA. For further information please contact MarinBio at info@marinbio.com or call 415 883 8000 or visit our website at www.marinbio.com.