Dr. Anita Joshi gave a lecture on moving a new drug or biologic candidate from pre-clinical testing to market. She described the multi-step process, including pre-clinical testing in test tubes and animals to determine safety, efficacy, and pharmacokinetics. Successful candidates then undergo clinical trials in three phases with humans to further evaluate these factors before regulatory review and potential marketing approval. The overall process takes an estimated 12 years and costs $5-8 million on average, with many candidates failing to reach later stages or approval.
From the test tube to the market: the drug development process
1. From the test tube… into
the market
Dr. Anita Joshi
Garware College, Pune – lecture for
Post graduate students
02/04/10
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New drug/ biologic
Candidate drug
5 batches
Pre-clinical testing IND Clinical trials NDADCGI
Candidate biologic
IBSC RCGM Pre-clinical testing Clinical trialsDCGI
MANUFACTURING AND
MARKETING
LICENSE
DCGI
In vitro
characterisation
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Pre-clinical testing
Done after In-vitro testing – characterization of
the molecule and safety perspectives – “risk”
Objective: preliminary efficacy, toxicity and
mechanism of action and pharmacokinetics of the
drug under investigation
In-vivo testing- rodent / non-rodent because a
drug may affect different species in different
ways
Done in GLP environments only, Schedule Y
A drug that successfully completes this phase
only has a 20% chance to make it to market
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Toxicological testing
The study of the adverse effects of
chemical, physical or biological agents on
living organisms and the ecosystem
Advantages-
chemical exposure can be precisely controlled
environmental conditions can be well-
controlled
virtually any type of toxic effect can be
evaluated
the mechanism by which toxicity occurs can be
studied
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In vivo testing
How much of the drug is absorbed into the
blood?
How is the drug broken down in the body?
What is the toxicity of the drug and its
breakdown products?
How quickly does the body excrete the drug
and its breakdown products?
Safe route for administration, safe dosage,
safe schedule
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In vivo testing critical parameters
Choice of animal – mice, rats, guinea pigs,
rabbits etc (Sprague Dawley rats, Wistar rats,
Swiss albino mice, New Zealand white rabbits,
monkeys, dogs)
Age of the animals
Gender
Dosage and route
Duration
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Efficacy
In case of a vaccine, the efficacy would be
defined by the potency of a vaccine
Immunogenecity studies – antibodies
generated in response to vaccine
Challenge tests
Safety tests
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Different types of toxicity tests
Most commonly used tests are
Acute Toxicity
Subacute toxicity
Subchronic Toxicity
Chronic Toxicity
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Acute Toxicity
Adverse effects of a substance after a
single dose or brief exposure
Observation period- 14 days
3 doses recommended- dose response
curve
Small grp of animals- 5 of each sex / dose
Exposures: fractionated dose or single
dose over 24hrs for oral and 4 hrs for
inhalation studies
LD50 calculated
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Sub acute and sub chronic
(repeated dose)
Repeated exposure for several weeks or several months
Two distinct situations need to be considered:
Prolonged exposure to a substance
Prolonged internal exposure because a substance
remains in the body for a long time
3 dose levels + control group; 2 different animal sps
10 of each sex per dose level
Observation 30 days for sub acute
Observation 90 days for sub chronic
Observed each day for signs of toxicity: weight change,
appetite, signs of disease or abnormal behavior.
Evaluation of effects and histopathology is conducted on all
animals.
This is outlined in ISO 10993-11.
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Chronic toxicity
Determines toxicity from exposure for a
substantial portion of a subject's life
Extend over a longer period of time and
involve larger groups of animals.
Two sps of animals
20 animals of each sex / dose level
3 dose levels
12-24 months
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Other toxicity tests
Reproductive toxicity – reproductive organs,
conception, birth
Developmental toxicity - embryotoxicity
Dermal toxicity
Occular toxicity – Draize test
Genotoxicity – Ames test, cell line based tests
Neurotoxicity
Carcinogenecity
In vitro testing
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Good Laboratory Practices
GLP - (guidelines are like GMP) for
laboratory and pre-clinical (i.e., animal)
studies
Defined in 21 CFR 58.
All about control and documentation/
implementation for the lab
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GLP
Requirement for a Study Director
Requirement for a Quality Assurance unit
Responsible for maintaining a Master Schedule Sheet of
all studies conducted
Responsible for inspecting the study during its conduct
Determine no deviations
Review final report for accuracy
Maintain records
Facilities designed to
Permit segregation necessary to ensure study integrity
including:
Areas for preparation of test and control articles
Routine and specialized analytical procedures
Separation of animal species and their proper
maintenance
Animals in different studies
Quarantine of new animals
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GLP
Equipment must be inspected, cleaned, and maintained,
including calibration
Reagents appropriately labeled
Test and control articles characterized for identity, strength
(potency), purity, and composition
Manufacturing of test article documented
Stability determined before or during study according to
written SOPs
SOPs for routine procedures (listed examples in 21 CFR
58.81)
Study protocol detailing specific study
Results recorded and raw data documented
Records (including raw data) maintained for specified time
periods
Final report written documenting procedures, results,
statistical analyses
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Pharmacokinetics
Pharmacokinetics describes how the
body affects a specific drug after
administration.
Pharmacokinetic properties of drugs may
be affected by elements such as the site of
administration and the concentration in
which the drug is administered.
These may affect the absorption rate.
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Pharmacokinetics
ADME measures the extent and rate of
Absorption, Distribution, Metabolism and
Excretion.
recent understanding about the drug-body
interactions brought about the inclusion of new
term Liberation. Now LADME.
Liberation- release of drug from the formulation.
Absorption -a substance entering the body.
Distribution - dispersion or dissemination of
substances throughout the fluids and tissues of
the body.
Metabolism- irreversible transformation of parent
compounds into daughter metabolites.
Excretion- elimination of the substances from the
body. In rare cases, some drugs irreversibly
accumulate in a tissue in the body.
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Pharmacodynamics
Study of the physiological effects of drugs on the
body or on microorganisms or parasites within or
on the body
Mechanisms of drug action and the relationship
between drug concentration and effect
There are 5 main drug actions:
depressing
stimulating
cytotoxicity
irritation
replacing substances
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Desired activity
The desired activity of a drug is mainly due to
one of the following:
Cellular membrane disruption
Chemical reaction
Interaction with enzyme proteins
Interaction with structural proteins
Interaction with carrier proteins
Interaction with ion channels
Ligand binding to receptors:
Hormone receptors
Neuromodulator receptors
Neurotransmitter receptors
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Undesirable effects of drugs
Increased probability of cell mutation
(carcinogenic activity)
A multitude of simultaneous assorted
actions which may be deleterious
Interaction (additive, multiplicative, or
metabolic)
Induced physiological damage, or
abnormal chronic conditions
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Clinical trials
Once the pre clinical trials are complete the data
is submitted to DCGI for approvals for a clinical
trial.
Research study to answer specific questions
about vaccines or new therapies or new ways of
using known treatments.
Safety and efficacy of drugs in humans
GCP – ensure safety of subjects, protection of
human rights, reliability of results and
maintenance of scientific quality
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The roadmap of a trial
In accordance with the GCPs ICH guidelines, Schedule Y,
Helsinki Declaration
Sponsor approaches CRO
Feasibility check
Investigators appointed
Protocol is designed
Ethics Committee approvals
Recruiting the volunteers – eligibility criteria set
Informed Consent forms
Starting the trials
Audits by sponsor
Completion of trials
Submission of data
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Experimental design of a trial
Randomized
Blind- The subjects involved in the study
do not know which study treatment they
receive.
Double-blind- the researchers also do not
know which treatment is being given to
any given subject to prevent biases
Placebo-controlled: The use of a placebo
(fake treatment) allows the researchers to
isolate the effect of the study treatment.
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Phase 1 trials
First stage of testing in humans
Done in a small group of healthy
volunteers (20 -100)
Objective: to assess the safety,
tolerability, pharmacodynamics,
pharmacokinetics of a drug
Single ascending dose studies
Multiple ascending dose studies
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Phase II trials
Typically done on larger groups – 100-300
Patients are enrolled for this phase
Phase II studies are sometimes divided into
Phase IIA and Phase IIB.
Phase IIA is specifically designed to assess dosing
requirements (how much drug should be given).
Phase IIB is specifically designed to study efficacy (how
well the drug works at the prescribed dose(s)).
When the development process for a new drug
fails, this usually occurs during Phase II trials
when the drug is discovered not to work as
planned, or to have toxic effects.
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Phase III trials
Much larger group 300-3000
Multi centric trials
Gold standard
gather additional information about
effectiveness and safety
evaluate overall benefit-risk relationship of
the drug
provide the basis for the precautionary
information that accompanies the drug
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The CTD
Drug has proved satisfactory after Phase III trials
•Trial results are usually combined into a large document containing
•a comprehensive description of the methods
•results of human and animal studies
•manufacturing procedures
•formulation details
•shelf life.
Regulatory Authorities for review- DCGI
Most drugs undergoing Phase III clinical trials can be marketed
under FDA norms with proper recommendations and guidelines
If any adverse effects are reported
the drugs need to be recalled immediately
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Phase IV- Post Marketing Surveillance Trial
Safety surveillance (pharmacovigilance)
Ongoing technical support of a drug after it receives permission to
be sold.
Required by regulatory authorities
May be undertaken for finding a new market for the drug
Study interactions with other drugs, or on certain new population
groups such as pregnant women
Rare or long-term adverse effects over a much larger patient
population and longer time period than was possible during the
Phase I-III clinical trials.
Harmful effects if discovered - drug being no longer sold, or
restricted to certain uses
Recent examples involve cerivastatin (brand names Baycol and
Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
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Performance of vaccine
Hemagglutinin inhibition assay (a
laboratory test used to measure the
amount of antibody present in a sample by
determining if the antibody inhibits
influenza virus from attaching to red blood
cells)
Microneutralization assay (a technique
used to determine if the level of antibody
in the sample inhibits the virus from
infecting cells grown in the laboratory)
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Pipeline of drug development
AstraZeneca (AZN) , Bristol-Myers Squibb Company (BMY) , Eli Lilly and
Company (LLY) , GlaxoSmithKline (GSK) , Merck (MRK) , Pfizer (PFE) ,
Sanofi-Aventis
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General trends
TIME REJECTION
PRECLINICAL 2-5 YRS 2.5
PHASE I 1-2 YRS 1.5 90%
PHASE II 2-3 YRS 2 50%
PHASE III 2-5 YRS 4 20%
REGULATORY 1-2 YRS 2 10%
ESTIMATED 12
TIME
EST. COSTS 5-8 MILLION USD
Notas do Editor
For example if a person drinks too much alcohol on a regular basis then their health may suffer as a result. The alcohol does not have a long biological half life but it is supplied on a regular basis to the body of the person For example if a person were to ingest radium much of it would be absorbed into the bones where it would exert a harmful effect on a person's health. The radium might cause a disturbance in the blood cell-forming part of the bone (bone marrow)
Reproductive Toxicity Reproductive toxicity testing is intended to determine the effects of substances on gonadal function, conception, birth, and the growth and development of the offspring. The oral route is preferred. Developmental toxicity testing detects the potential for substances to produce embryotoxicity and birth defects Dermal Toxicity Dermal toxicity tests determine the potential for an agent to cause irritation and inflammation of the skin. This may be the result of direct damage to the skin cells by a substance. It may also be an indirect response due to sensitization from prior exposure. Ocular Toxicity Ocular toxicity is determined by applying a test substance for one second to the eyes of 6 test animals, usually rabbits. The eyes are then carefully examined for 72-hours, using a magnifying instrument to detect minor effects. The ocular reaction may occur on the cornea, conjunctiva, or iris. It may be simple irritation that is reversible and quickly disappears or the irritation may be severe and produce corrosion, an irreversible condition. The eye irritation test is commonly known as the "Draize Test." This test has been targeted by animal welfare groups as an inhumane procedure due to pain that may be induced in the eye. The test allows the use of an eye anesthetic in the event pain is evident. The Draize Test is a reliable predictor of human eye response. However, research to develop alternative testing procedures that do not use live animals is underway. While some cell and tissue assays are promising, they have not as yet proved as reliable as the animal test. Genetic Toxicity Genetic toxicity is determined using a wide range of test species including whole animals and plants (e.g., rodents, insects, and corn), microorganisms, and mammalian cells. A large variety of tests have been developed to measure gene mutations, chromosome changes, and DNA activity. The most common gene mutation tests involve:
A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials . Types of observational studies in epidemiology such as the cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies , the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases. A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health. Currently, some Phase II and most Phase III drug trials are designed as randomized, double blind , and placebo -controlled. Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo. Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study. Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment. Of note, during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). In other words, when a treatment exists that is clearly better than doing nothing for the subject ( i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy. Although the term "clinical trials" is most commonly associated with the large, randomized studies typical of Phase III, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university.
Phase I trials are the first stage of testing in human subjects. Normally, a small (20-100) group of healthy volunteers will be selected. This phase includes trials designed to assess the safety ( pharmacovigilance ), tolerability, pharmacokinetics, and pharmacodynamics of a drug. These trials are often conducted in an inpatient clinic, where the subject can be observed by full-time staff. The subject who receives the drug is usually observed until several half-lives of the drug have passed. Phase I trials also normally include dose-ranging , also called dose escalation, studies so that the appropriate dose for therapeutic use can be found. The tested range of doses will usually be a fraction of the dose that causes harm in animal testing . Phase I trials most often include healthy volunteers. However, there are some circumstances when real patients are used, such as patients who have terminal cancer or HIV and lack other treatment options. Volunteers are paid an inconvenience fee for their time spent in the volunteer centre. Pay ranges from a small amount of money for a short period of residence, to a larger amount of up to approx $6000 depending on length of participation. There are different kinds of Phase I trials: SAD Single Ascending Dose studies are those in which small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time. If they do not exhibit any adverse side effects, and the pharmacokinetic data is roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the Maximum tolerated dose (MTD). MAD Multiple Ascending Dose studies are conducted to better understand the pharmacokinetics & pharmacodynamics of multiple doses of the drug. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to understand how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level. Food effect A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study , with volunteers being given two identical doses of the drug on different occasions; one while fasted, and one after being fed.
Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorised as "Phase IIIB studies."[19][20] While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory agencies such as FDA (USA), or the EMEA (European Union), for example. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities[3] in different countries. They will review the submission, and, it is hoped, give the sponsor approval to market the drug. Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines, but in case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.[21]