drug discovery process and regulatory aspects.pdf

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  • By: Maged Wasfy

    Lecturer of Pharmacology Faculty of Pharmacy and Drug Manufacturing

    Pharos University in Alexandria

    Regulatory Aspects of Safety in Process of drug Discovery & Development

    Forensic Chemistry (PHR 476) Lecture of week 12

  • Regulatory Aspects of Safety in Process of drug Discovery & Development

  • Drug discovery and development is a long and complex process.

    Only one of every 5,000-10,000 molecules screened in the laboratory ever makes it to market as a new drug.

    FDA & Research-based pharmaceutical companies take extraordinary measures to ensure the safety and efficacy of all

    approved prescription medicines.

    To ensure patient safety, FDA and the pharmaceutical company follow careful scientific procedures in four distinct stages:

    1. Preclinical safety assessment

    2. Pre-approval safety assessment in humans

    3. Safety assessment during FDA regulatory review

    4. Post-marketing safety surveillance.

    Regulatory Aspects of Safety in Process of drug Discovery & Development

  • 1. Preclinical Safety Assessment

    The relative safety of newly synthesized compounds is initially evaluated in both in vitro and in vivo tests.

    If a compound appears to have important biological & pharmacological activity special tests are conducted to evaluate its safety in the major organ systems (for example, the liver;

    the central nervous, cardiovascular, and respiratory systems).

    Other organ systems are evaluated when potential problems appear.

    The goal of preclinical animal studies are:

    A. To ensure that a drug is safe enough to be tested in humans.

    B. Characterize any relationship between increased doses of a drug

    and toxic effects in the animals.

    Regulatory Aspects of Safety in Process of drug Discovery & Development

  • 2. Pre-Approval Safety Assessment in Humans (clinical trials)

    A drug sponsor can begin clinical trials in humans once FDA is satisfied that the preclinical animal data do not show an

    unacceptable safety risk to humans.

    New Drug Application (NDA) seeking FDA regulatory review to market a new product.

    Each clinical trial evaluates:

    A. Safety & adverse effects regardless of the stated objective of

    the trial.

    B. Effect of new drug on the quality-of-life

    C. Pharmacoeconomic of the new drug.

    All harmful reactions are reported to FDA and, when appropriate, the information is incorporated in a drugs package labeling.

    Regulatory Aspects of Safety in Process of drug Discovery & Development

  • 2. Pre-Approval Safety Assessment in Humans (clinical trials)

    The average NDA for a novel prescription medicine is based on approximately 70 clinical trials involving over 4,000 patients.

    Clinical trials are conducted in three stages:

    A.Phase I:

    Drugs are evaluated for safety in healthy volunteers using single dose &multiple dose

    B.Phase II:

    To evaluate the safety and efficacy of a drug using patients instead of healthy volunteers.

    C.Phase III:

    These large trials evaluate safety and efficacy in groups of patients (with the disease to be treated) from different populations (elderly,

    patients with multiple diseases, those who take other drugs, and

    patients whose organs are impaired).

    Regulatory Aspects of Safety in Process of drug Discovery & Development

  • 3. Safety Assessment During FDA Regulatory Review

    A sponsor submits an NDA to FDA for approval to manufacture, distribute, and market a drug based on the safety and efficacy data

    obtained during the clinical trials.

    FDA usually completes its review of a standard drug in 10 to 12 months. 120 days prior to a drugs anticipated approval, a sponsor must provide the agency with a summary of all safety information in

    the NDA, along with any additional safety information obtained

    during the review period.

    The addition of 600 new reviewers made possible by the user fees paid by pharmaceutical companies has enabled FDA to approve new

    drugs while maintaining high safety standards.

    Regulatory Aspects of Safety in Process of drug Discovery & Development

  • 4. Post-Marketing Safety Surveillance

    Monitoring and evaluating a drugs safety become more complex after it is approved and marketed as drug will be taken by many

    more patients and physicians are free to use it in different doses,

    different dosing regimens and different patient populations.

    Adverse reactions that occur in fewer than 1 in 3,000 to 5,000 patients are unlikely to be detected in pre-approval investigational

    clinical trials, and may be unknown at the time a drug is approved.

    These rare adverse reactions are more likely to be detected when large numbers of patients use a drug after it has been approved.

    If the drug shows serious adverse effects, FDA has its authority to RECALL the drug from the market.

    Regulatory Aspects of Safety in Process of drug Discovery & Development

  • Preclinical Safety Assessment (Toxicity Testing )

  • Toxicity testing is the structural unit of two branches of


    A.Descriptive toxicology:

    It is concerned with toxicity testing in experimental animals and used to evaluate the risks posed to humans by exposure to specific


    B.Regulatory toxicology:

    It is concerned with deciding, on the basis of the data provided by mechanistic and descriptive toxicologists, whether a drug or

    another chemical poses a sufficiently low risk to be marketed for a

    stated purpose.

    Preclinical Safety Assessment (Toxicity Testing )

  • Classification of Toxicity Studies

    1. Acute Toxicity studies (Limit Tests, LD50, LC50, ED50, MTD,


    2. Subchronic Toxicity studies

    3. Chronic Toxicity studies

    4. Special toxicity studies:

    A. Tests for Developmental toxicity ( teratogenicity).

    B. Tests for Reproductive Toxicity

    C. Tests for Mutagenicity

    D. Tests for Carcinogenicity

    E. Tests for Neurotoxicity & Behavioral toxicity.

    F. Tests for Immunotoxicity

  • 1- Acute Toxicity Studies


    It is studying of the adverse effects occurring within a short time of administration of a single dose or multiple doses

    given within 24 hours.

    Objectives of Acute toxicity studies are:

    1.Identify the symptoms & possible mode of action of relative

    toxicity of the compound.

    2.To determine the existence of species differences.

    3.Give information for further toxicity testing (i.e define more

    precisely the doses to be used in subchronic toxicity tests)

  • 1- Acute Toxicity Studies

    Parameters obtained from Acute toxicity testing:

    1. LD50 (Median lethal dose)

    The calculated dose of a chemical that causes death in 50% of the tested animals after acute, single exposure.

    For inhaled chemicals, median lethal dose is expressed as LC50 (median lethal concentration) which is median concentration to

    which animals are exposed for a fixed time that will kill 50% of the


    2. NOAEL ( Non Observed Adverse Effect Level).

    The highest dose in a toxicity study at which no toxic or adverse effects are observed.

    3. MTD (Maximum tolerated dose)

    The highest dose of a chemical that when administered to a group of test animals does not increase the death rate during a

    long-term study.

  • 1- Acute Toxicity Studies Experimental Design of Acute toxicity testing: 1. Animal species: At least 2 species are required Rats and mice are usually used, but sometimes dogs and rabbits are

    also included.

    2. Animal number & gender: At least (8-12) of each species, (4-6) of each sex.

    3. Route of administration: The chemical should be administered by the same route with which

    human would be administered. (e,g: Oral gavage, Ocular, Dermal, Intraperitoneal, lnhalation, intravenous, Intramuscular, Intranasal, Subcutaneous)

    Sometimes, we use more than two route of administration to assess potential hazardous effects of chemical handling by human.

    e.g: if the route of human exposure would be oral, acute dermal, eye, and inhalation studies may be indicated to assess the hazard to personnel's handling the compound.

  • 1- Acute Toxicity Studies Experimental Design of Acute toxicity testing: 4. Dosing : single dose or multiple doses

    5. Animal Monitoring: The animals are observed for 14 days after chemical administration. Observations include:

    A. Recording of any serious symptomatic adverse effects.

    B. Recording the number of animals dying during observation period, to

    calculate LD50.

    C. Any animals that haven't already died are then sacrificed and

    dissected. Postmortem examination

    In general, all animals dying during the observation period and all surviving animals should be autopsied by a qualified pathologist. The autopsy should include gross and histopathological examination of all organs.

  • 1- Acute Toxicity Studies

    Examples of Acute toxicity testing

    A. Inhalation test

    It is used for assessment of the toxic hazard of agents whose principal route of exposure is via inhalation and to Study of the

    comparative toxicity of agents administered by different routes.

    LC50 (median lethal concentration) is the parameter