Drug Development Process

1. Discovery

Target Identification

  • Targets can be either proteins, genes, or RNAs.
  • Targets must be:
    • accessible to the putative drug molecule
    • elicit a biological response upon binding , and
    • the biological response must be measurable in vitro and in vivo

Processes for Identifying Targets

  • Data mining (bioinformatics approach)
    • Publications
    • Patents
    • Gene Expression Data
    • Proteomics Data
    • Transgenic Phenotyping
    • Compound profiling data
  • Examination of mRNA/Protein Levels to Determine Expression in a Disease and Correlation with Disease Exacerbation or Progression
  • Genetic Associations-(links between genetic polymorphism and risk of disease or disease progression)
  • Phenotypic Screening (e.g. phage display)

Target Validation

  • Small bioactive molecules that interact with and functionally modulated effector proteins
  • Antisense technology
  • Transgenic animals
    • gene knock-outs
    • gene knock-ins (non-enzymatically functioning protein replaces endogenous protein
  • siRNA
  • Monoclonal antibodies for cell surface and secreted proteins

Hit Identification

  • Biological Assay Development to Identify Molecules with Activity at Target
  • Screening of Compound Libraries (1 IN 10,000 makes it to market)
    • High Throughput
    • Focused Screen
    • Fragment Screen
    • Structural Aided Drug Design
    • Virtual Screen
    • Physiological Screen
    • NMR Screen
  • Defining a Hit Series

Lead Development

  • Refine "hit series" of compounds to produce more potent and selective compounds with PK properties adequate to test in in vivo models
    • Intensive Structure Activity Relationship (SAR) investigations

2. Nonclinical development

Nonclinical Study Design Relative to Clinical Trial(s)

  • Understanding the clinical trial design is critical in the design of the nonclinical studies.
  • Minimally, knowledge of the clinical dosing route, frequency, duration, and anticipated dose range are needed to adequately design the nonclinical studies.
  • Overall purpose of nonclinical development is to provide information regarding:
    • Exposure response relationship (a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effects to a defined exposure is known).
    • Potential drug toxicities
    • Safety margins
    • Estimates Identification of target organ toxicities
    • Evaluation of reversibility of observed effects

Animal Species Selection Considerations

  • Issues to consider
    • Species difference in absorption, distribution, metabolism and excretion (ADME) of the specific drug (see below for further information about ADME)
    • Expression of relevant receptors or epitopes in a specific species
    • Pharmacological activity
    • Bioavailability
  • Small Molecules-'Most Appropriate Species'
    • in vitro metabolic profiling of products produced from the drug (liver microsomes from a full spectrum of species-mouse, rat, dog, mini-pig, nonhuman primate, human)
  • Biopharmaceuticals-'Most Relevant Species'
    • in vitro and in vivo assays that demonstrate the ability of the drug to elicit a pharmacological effect

Validated Analytical Methods

It is important to develop and qualify/validate these assays early in the development process for concentration and stability, homogeneity as necessary
  • Methods required to determine the amount of drug in the preparations administered to animals
    • One method for each vehicle used-i.e. one method for general toxicology and safety pharmacology studies, one method for in vitro genetic toxicology studies, one method for hERG assay
  • Methods required to determine the amount of drug in serum/plasma in animals
    • One method for rodent, nonrodent and human
  • Methods required to determine the presence of antibodies against the drug in serum of animals for biopharmaceuticals

Primary Pharmacology Studies

  • Primary PD studies (in vivo and/or in vitro) are intended to investigate the mode of action and/or effects of a substance in relation to its desired therapeutic target.
  • Such studies are generally conducted during the discovery phase of pharmaceutical development and as such, are not generally conducted in accordance with Good Laboratory Practices (GLP).

Drug Metabolism/Pharmacokinetic Studies (DMPK)

  • DMPK is how drug is absorbed, where it enters the body, what it breaks down into and how the body eliminates it.
  • Investigations to provide information on
    • Systemic exposure to the animals by measurement of blood levels (=Absorption)
    • Distribution and retention within major organs of the rodent by whole body autoradiography (=Distribution)
    • Major metabolic pathways through in vitro and in vivo investigations for demonstration of major metabolic similarity / dissimilarity between the animal species used in toxicity studies and humans (=Metabolism)
    • Rate and routes of elimination (=Excretion)
    • Absorption
      • Single dose Pharmacokinetics (p.o.; i.v.) in several animal species
    • Distribution
      • Mass balance
      • Quantitative whole body autoradiography (QWBA)
      • Protein binding
      • Red cell partitioning and brain penetration
    • Metabolism (stability & pattern; identification)
      • in vitro: microsomes; hepatocytes of several species
      • CYP induction (metabolizing enzymes and transporters)
      • in vivo metabolism
    • Excretion
      • Biliary; Urinary
    • Screen of different Formulation
      • Bioavailibility

Pre-IND meeting

After primary pharmacology and basic ADME data in animals are available but before performance of toxicology studies to support an IND, it is time to review with the FDA the overall plan for the toxicology studies, the initial clinical plan and the basic manufacturing process(es). More information

Nonclinical Studies for Small Molecules-(Drugs)

The definition of the term drug in section 201(g)(1) of the FD&C Act includes, among other things, "articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease . . ." and "articles (other than food) intended to affect the structure or any function of the body of man or other animals."

General Toxicology Studies

  • The design of any nonclinical package to support an IND or BLA submission depends on test article type, indication, route, and the design of the initial clinical plan.
  • These studies must be performed in compliance with Good Laboratory Practices (GLPs)
  • Dose Selection-a control and three dose levels are generally evaluated
    • Low dose should provide No Observed Adverse Effect Level (NOAEL) and generally selected based on an acceptable margin of safety with regard to the proposed clinical starting dose.
    • The high dose should define:
      • The Maximum Tolerated Dose (MTD)-the highest dose of a drug or treatment that does not cause unacceptable side effects and identify target organ toxicities; or
      • The Maximum Feasible Dose (MFD)- limiting dose that achieves large exposure multiples or saturation of exposure
    • The mid dose should characterize the dose-response relationship
  • Non-GLP Dose Range Finding (DRF) study in rodents and nonrodents
    • Limited number of animals
    • Route of administration the same as proposed for clinical studies
    • Dose level escalated to define MTD in single dose and short repeat dose phase
  • GLP Repeat Dose Toxicology Studies
    • Larger number of animals to provide statistical power
    • Route of administration the same as proposed for clinical studies
    • Dose levels dependent on data from DRF studies
    • Duration dependent on design of Clinical Trial
    • Toxicokinetics
    • Recovery arm to determine whether effects increase, decrease or remain the same following cessation of dosing
  • Other studies dependent on the route of administration
    • Local tolerance studies
    • Delayed hypersensitivity studies (dermal products)
    • Hemocompatiblity (intravenous products)

Safety Pharmacology Studies

  • Assessment of drug to exert a pharmacological effect on critical organ systems, generally at lower dose than toxicology studies to identify subtle effects.
  • These studies must be performed in compliance with Good Laboratory Practices (GLPs)
    • Cardiovascular in nonrodent
      • Same species as nonrodent species in toxicology studies
      • Telemetry of animals
      • Collection of data for 24 hours following dose administration
    • in vitro hERG
      • Assay determines possible interaction of drug with the hERG potassium channel on mammalian hearts
      • Blockage of hERG channel can cause QT prolongation which can lead to ventricular arrhythmia (Torsades de Pointes)
    • Central Nervous System Study in Rodents
      • Same rodent specifies as selected for the toxicology studies
      • Evaluation of locomotion, grip strength, hind-limb splay, pain perception, reaction to stimuli etc.
    • Respiratory Study in Rodents
      • Same rodent specifies as selected for the toxicology studies
      • Rodents placed in plethysmograph (instrument for measuring changes in volume within an organ or whole body usually resulting from fluctuations in the amount of blood or air it contains).
      • Measure respiratory rate, tidal volume, minute volume etc.
    • Other studies depending on pharmacology of the drug may be required
      • Renal Safety Pharmacology
      • Gastrointestinal Motility

Genetic Toxicology Battery

  • GLP compliant
    • Ames test-bacterial assay to determine if drug can cause point mutations
    • Chromosomal aberration
      • in vitro assay with S9 metabolic system
      • Evaluates the potential for the drug to damage chromosomes (clastogenicity)
    • in vivo Micronucleus test in rats/ mice
      • in vivo study to determine drugs potential for clastogenicity
      • Can be deferred to Phase 2 but generally done along with other studies

3. Investigational New Drug (IND) Application Submission

FDA's Role

  • FDA's role in the development of a new drug begins when the drug's sponsor (usually the manufacturer or potential marketer), having screened the new molecule for pharmacological activity and acute toxicity potential in animals, wants to test its diagnostic or therapeutic potential in humans.
  • At that point, the molecule changes in legal status under the Federal Food, Drug, and Cosmetic Act and becomes a new drug subject to specific requirements of the drug regulatory system.

FDA's Objectives in Reviewing an IND

  • FDA has two primary objectives in reviewing an IND: (1) to assure the safety and rights of subjects in all phases of an investigation and (2) in phases 2 and 3, to help assure that the quality of the scientific evaluation of the drug is adequate to permit an evaluation of the drug's effectiveness and safety (21 CFR 312.22).


  • An Investigational New Drug Application (IND) is a request for authorization from the Food and Drug Administration (FDA) to administer an investigational drug or biological product to humans.
  • An IND must be authorized prior to interstate shipment and administration of any new drug or biological product that is not the subject of an approved New Drug Application or Biologics/Product License Application
  • IND Regulations are found in - Title 21 of the Code of Federal Regulations (CFR), Part 312 (21 CFR 312 ).
  • Guidance on INDs is provided on the FDA web page

IND Regulations in Title 21 of the Code of Federal Regulations

  • IND Regulations are found in Title 21 of the Code of Federal Regulations (CFR), Part 312
  • Additional regulations that apply to INDs are found in 21 CFR as follows:
    21CFR Part 312 Investigational New Drug Application
    21CFR Part 314 INDA and NDA Applications for FDA Approval to Market a New Drug (New Drug Approval)
    21CFR Part 316 Orphan Drugs
    21CFR Part 58 Good Laboratory Practice for Nonclinical Laboratory (Animal) Studies
    21CFR Part 50 Protection of Human Subjects
    21CFR Part 56 Institutional Review Boards
    21CFR Part 201 Drug Labelling
    21CFR Part 54 Financial Disclosure by Clinical Investigators

When is an IND Required

Categories of INDs

  • INDs fall into two categories:
    • Commercial, submitted mainly by companies seeking marketing approval for a new drug.
    • Research (non-commercial).
  • The majority of INDs are filed for non-commercial research and are of three main types – Investigator IND, Emergency Use IND, and Treatment IND

Information to Include in an IND

  • The IND application must contain information in three broad areas:
    • Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
    • Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.
    • Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations

Format of an IND

Investigator IND

  • Sponsor of an IND application is the party who submits the application to FDA. In the absence of any other sponsor (e.g. pharmaceutical company), the investigator conducting the proposed clinical investigation is the sponsor of the IND application.
  • FDA Guidance for investigators wishing to file an IND should check the FDA website for extensive guidance.
  • FDA has two primary objectives in reviewing an IND: (1) to assure the safety and rights of subjects in all phases of an investigation and (2) in phases 2 and 3, to help assure that the quality of the scientific evaluation of the drug is adequate to permit an evaluation of the drug's effectiveness and safety (21 CFR 312.22 ).
  • In general, the IND regulations in part 312 require that human research studies be conducted under an IND if all of the following conditions exist:
    • The research involves a drug as that term is defined in section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 321(g)(1)).
    • The research is a clinical investigation as defined in the IND regulations (21 CFR 312.3 ).
    • The clinical investigation is not otherwise exempt from the IND requirements in part 312

Review of IND by FDA After Initial IND Submission

  • Once an IND is submitted, there is a mandatory 30 calendar day review period from the date FDA notes as the day of receipt.
    • If an IND is submitted in paper, the date of receipt is the day when the IND is delivered to the document room at the FDA.
    • If an IND is submitted electronically, generally before 4:00 p.m., the day of receipt is the same day it was submitted. If after 4:00 pm, then the receipt date is generally the following day.
  • The FDA will send a letter in approximately a week to 10 days acknowledging receipt and noting the day which FDA considers the 30th day after the submission receipt.
  • The sponsor must wait to the 30th day as provided by FDA before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

Clinical Hold of an IND

  • If FDA considers there to be an unreasonable risk to the trial as provided in the IND, the IND will be placed on Clinical Hold. There are two types of Clinical Hold.
    • Complete Clinical Hold: A delay or suspension of all clinical work requested under an IND.
    • Partial Clinical Hold: A delay or suspension of only part of the clinical work requested under the IND (e.g., a specific protocol or part of a protocol is not allowed to proceed; however, other protocols or parts of the protocol are allowed to proceed under the IND).
  • A clinical hold (including a partial clinical hold) involves the Agency (1) requiring additional information and/or data, (2) reviewing the additional information and/or data, and (3) after the review, informing the sponsor that they can proceed.
  • The Agency may request additional information and/or data from the Sponsor but unless the FDA specifically notes the IND has been placed on Clinical Hold, the sponsor does not have to wait for FDA review to proceed.

Complete Response to an IND Clinical Hold

  • A Sponsor must submit a "Complete Response" to the IND for the IND to be released from the Clinical Hold. The FDA definition of a Complete Response is provided below:
    • Applicant's Complete Response to an IND Clinical Hold: A response from the applicant in which all clinical hold issues identified in the clinical hold letter have been addressed.
  • After review of the Complete Response by the FDA, a letter will be sent to the Sponsor (applicant). FDA's Response to a Sponsor's complete response will be followed up with a letter from the FDA. The letter will note either of the following:
    • The Sponsor (applicant) is allowed to proceed under the IND as proposed by the applicant (i.e., the clinical hold is lifted),
    • The Sponsor (applicant) is allowed to proceed with specific restrictions not proposed by the applicant (i.e., a partial hold), or
    • The Sponsor (applicant) is informed that studies under the IND may still not proceed.
  • In the latter two cases, the letter will set forth why the clinical hold is being maintained. This letter should be issued to the applicant within 30 calendar days of receipt of the applicant's complete response.
  • When FDA lifts the Clinical Hold, they will telephone the Sponsor to note the lift of the hold and send a follow-up letter noting the release of the clinical hold.

4. Phase 1

  • Begin 30 days after submission of IND providing FDA has not placed a "clinical hold" on development.
  • It involves 20-80 healthy adult subjects
  • Duration: 1 year
  • Cost: $100,000 - $1,000,000
  • Objective: to determine safety and dosage

5. Phase 2

  • Begin 30 days after submission of phase 2 clinical study providing FDA has not placed a "clinical hold" on development.
  • It involves up to several hundred subjects with disease/condition
  • Duration: several months to 2 year
  • Cost: $1,000,000 - $20,000,000
  • Objective: to determine efficacy and side effects

6. Phase 3

  • Begin 30 days after submission of phase 3 clinical study providing FDA has not placed a "clinical hold" on development.
  • It involves 300-3,000 subjects who have the disease or condition
  • Duration: 1-4 years
  • Cost: $20,000,000 - $40,000,000
  • Objective: to determine efficacy and monitoring of adverse reactions

7. FDA Marketing Application filing

Content coming soon...

8 - Drug approved for specific use in patients