Regulatory requirements for drug approval
Contents
• Drug development teams
• Non-clinical drug development
• Pharmacology
• Drug metabolism and toxicology
• General considerations of IND, Investigator’s Brochure,
NDA
• Clinical research/BE studies
• Clinical Research protocols
• Biostatistics in pharmaceutical product development
• Data presentation for FDA submissions
• Management of clinical studies
Non-clinical/pre-clinical)
drug development
• This phase primarily aims to identify which candidate
therapy has the greatest probability of success, assess its safety, and build
solid scientific foundations before transition to the clinical development
phase.
• The drug candidate should meet non-medical objectives,
including defining the intellectual property
rights and making enough medicinal product available
for clinical trials.
• The non-clinical development of a medicine is complex and
regulatory-driven.
Studies in non-clinical development are performed:
• In silico: ‘performed on computer or via computer
simulation’, e.g. predicting the toxicology profile of a product using its
chemical structure from data-based approaches.
• In vitro (Latin for ‘within the glass’): performing a
procedure in a controlled environment outside of a living organism, e.g. use of
hepatocyte (cells from the liver) cultures for metabolism studies.
• In vivo (Latin for ’within the living’): experimentation
using a whole, living organism as opposed to tissues or cells, i.e. animals,
humans or plants.
Objectives:
• Once a candidate compound is identified, the non- clinical
development should start answering the following questions, and answers will
come from specific assessments/studies:
• Does it work? → Efficacy assessment
• How will it be delivered and how will the body react?
→profiling
• Is it safe? → toxicology/safety
• Is the manufacture viable and controllable?
Non-clinical development activities can continue throughout
the life-cycle of the product, although the earlier these questions are
answered, the easier it is to identify the profile of the patient who will
benefit most.
• Provide individual study reports, including pharmacology,
toxicology, ADME studies.
• Effects related to the therapeutic indication, such as the
pharmacodynamics ED50 in dose- ranging studies and the mechanism of action (if
known)
• Interactions with other drugs (or cross-reference the
location of the information in any of the above subsection
Human
Pharmacokinetics and bioavailability
• Data from Phase I safety and tolerance studies in healthy
volunteers
• Summary of analytical method used in in-vivo bio-
pharmaceutic study
• Pilot or background studies
• Bio-availibility or bioequivalence studies
• Pharmacokinetic studies
• In vitro studies
Microbiology
Includes for anti-infective drug product. It requires the
following technical information and data:-
• A complete description of the biochemical basis of the
drug action on microbial physiology
• The drugs antimicrobial spectrum
• Describe any known mechanism of resistance to the drug and provide information/data of any
known epidemiologic studies demonstrating prevalence to resistance factor
• Clinical microbiology laboratory methods
Assure the sterility of the product through the
manufacturing process – especially important with injectable drug products.
Safety Data
• Statements in draft labeling
• Contra indications
• Warnings
• Precautions
• Adverse events
Statistical
Data
• All controlled clinical trial reports
• Integrated efficacy and safety summaries
• Integrated summary of risks and benefits
• CASE REPORT
TABULATION:- Includes complete tabulation for each patient from every
adequately are well controlled phase II and Phase III efficacy, clinical pharmacology
study. It also tabulation of safety data from all clinical studies.
• CASE REPORT
FORMS:- Includes the
complete CRF for
each patient who died during a clinical study or adverse event,
regardless of whether the AE is considered to be related to the study drug,
even if the patient was receiving a placebo or comparative drug.
Inspections/Testing
Assure manufacturing facilities are in compliance with
current good manufacturing practices (cGMPs)
Assure bioequivalence sites are in compliance with current
good clinical practices (cGCPs)
Conducted primarily by Field/Office of Regulatory Affairs
with support from Center
(Office of Compliance) and assigned geographically
Labs are in the Office of Regulatory Affairs and the
Center
Bioequivalence
• A generic drug is considered to be bioequivalent to the
brandname drug if:
• The rate and extent of absorption do not show a
significant difference from listed drug, or
• The extent of absorption does not show a significant
difference and any difference in rate is intentional or not medically
significant.
Regulation
by government agencies
• Concerns related to the efficacy and safety of drugs have
caused most governments to develop regulatory agencies to oversee development
and marketing of drug products and medical devices.
• Use of any drug carries with it some degree of risk of an
adverse event. For most drugs the risk-to-benefit ratio is favorable; that is,
the benefit derived from using the drug far outweighs the risk incurred from
its use. However, there have been
unfortunate circumstances in which drugs have caused considerable harm.
• The harm has come from drug products containing toxic
impurities, from drugs with unrecognized severe adverse reactions, from
adulterated drug products, and from fake or counterfeit drugs.
• Because of these issues, effective drug regulation is
required to ensure the safety and efficacy of drugs for the general public.
• The process of drug regulation has evolved over time.
• Laws regulating drug marketing and development, government
regulatory agencies with oversight of drug development and use, drug evaluation
boards, drug information centres, and quality control laboratories have become
part of the cooperative venture that produces and develops drugs.
• In some countries drug laws omit or exempt certain areas of
pharmaceutical activity from regulation. For example, some countries exempt
herbal or homeopathic products from regulation.
• In other countries there is very little regulation imposed
on drug importation. Over time, the scope of drug laws and the authority vested
in regulatory agencies have gradually expanded.
• In some instances, strengthening of drug laws has been the
result of a drug-related catastrophe that prompted public demand for more
restrictive legislation to provide more protection for the public. One such
example occurred in the 1960s with thalidomide
that was prescribed to treat morning sickness in pregnant women.
• At other times the public has perceived that drug regulation
and regulatory authorities have been too restrictive or too cautious in
approving drugs for the market.
• This concern typically has been related to individuals
with serious or life-threatening illnesses who might benefit from drugs that
have been denied market approval or whose approval has been inordinately
delayed because regulations are too strict.
• At times, governments have responded to these concerns by
streamlining drug laws and regulations. Examples of types of drugs given
expedited approval are cancer drugs and AIDS drugs.
• Regulatory measures that make rapid approval of new drugs
paramount sometimes have led to marketing of drugs with more toxicity than the
public finds acceptable. Thus, drug regulations can and probably will remain in
a state of flux, becoming more lax when the public perceives a need for new
drugs and more strict following a drug catastrophe.
• Current Federal law requires that a drug be the subject of
an approved marketing application before
INVESTIGATIONAL
NEW DRUG
IND
• Current Federal law requires that a drug be the subject of
an approved marketing application before it is transported or distributed
across state lines.
• Because a sponsor will probably want to ship the
investigational drug to clinical investigators in many states, it must seek an
exemption from that legal requirement.
• The IND is the means through which the sponsor technically
obtains this exemption from the FDA.
• During a new drug's early preclinical development, the sponsor’s
primary goal is to determine if the product is reasonably safe for initial use
in humans, and if the compound exhibits pharmacological activity that justifies
commercial development.
• When a product is identified as a viable candidate for
further development, the sponsor then focuses on collecting the data and
information necessary to establish that the product will not expose humans to
unreasonable risks when used in limited, early-stage clinical studies.
• 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.
Types of
IND
There are three IND types:
• An Investigator IND is submitted by a physician who both
initiates and conducts an investigation, and under whose immediate direction
the investigational drug is administered or dispensed. A physician might submit a research IND to
propose studying an unapproved drug, or an approved product for a new
indication or in a new patient population.
• Emergency Use IND allows the FDA to authorize use of an
experimental drug in an emergency situation that does not allow time for
submission of an IND in accordance with 21CFR, Sec. 312.23 or Sec. 312.20. It is also used for patients who do
not meet the criteria of an existing study protocol, or if an approved study
protocol does not exist.
• Treatment IND is submitted for experimental drugs showing
promise in clinical testing for serious or immediately life-threatening
conditions while the final clinical work is conducted and the FDA review takes
place.
There are two IND categories:
• Commercial
• Research (non-commercial)
The IND application contain information in three 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 (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.
• Once the IND is submitted, the sponsor must wait 30
calendar days 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.
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