MODULE - 7

Validation and regulation

• Validation is the process of establishing documentary evidence demonstrating that a procedure,
process, or activity carried out in testing and then production maintains the desired level of
compliance at all stages.
• In the pharmaceutical industry, it is very important that in addition to final testing and compliance
of products, it is also assured that the process will consistently produce the expected results.
• The desired results are established in terms of specifications for outcome of the process.
• Qualification of systems and equipment is therefore a part of the process of validation.
• Validation is a requirement of food, drug and pharmaceutical regulating agencies such as the US
FDA and their good manufacturing practices guidelines
• Process validation is defined as the collection and evaluation of data, from the process design stage
through commercial production, which establishes scientific evidence that a process is capable of
consistently delivering quality product. Process validation involves a series of activities taking place
over the lifecycle of the product and process
• FDA has the authority and responsibility to inspect and evaluate process validation performed by
manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing require
that drug products be produced with a high degree of assurance of meeting all the attributes they
are intended to possess
 Syllabus

• Validation and regulation, drug information, ICD and

DRG,
• designing of clinical studies,
• stability tests, analytical procedures, bioanalytical
methods of human studies,
• specification for new drugs and products NDA
application and classification to market a new drug
• Post approval surveillance.
 Process Validation and Drug Quality
• Effective process validation contributes significantly to assuring drug quality.
• The basic principle of quality assurance is that a drug should be produced that is fit for its intended
use.
• This principle incorporates the understanding that the following conditions exist:
– Quality, safety, and efficacy are designed or built into the product.
– Quality cannot be adequately assured merely by in-process and finished-product inspection or
testing.
– Each step of a manufacturing process is controlled to assure that the finished product meets
all quality attributes including specifications.
• process validation activities can be described in three stages.
– Stage 1 – Process Design: The commercial manufacturing process is defined during this stage
based on knowledge gained through development and scale-up activities.
– Stage 2 – Process Qualification: During this stage, the process design is evaluated to determine
if the process is capable of reproducible commercial manufacturing.
– Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine
production that the process remains in a state of control.
 Process Validation and Drug Quality
• Before any batch from the process is commercially distributed for use by consumers, a
manufacturer should have gained a high degree of assurance in the performance of the
manufacturing process such that it will consistently produce APIs and drug products meeting those
attributes relating to identity, strength, quality, purity, and potency.
• The assurance should be obtained from objective information and data from laboratory-, pilot-,
and/or commercialscale studies. Information and data should demonstrate that the commercial
manufacturing process is capable of consistently producing acceptable quality products within
commercial manufacturing conditions.
• A successful validation program depends upon information and knowledge from product and
process development. This knowledge and understanding is the basis for establishing an approach
to control of the manufacturing process that results in products with the desired quality attributes.
 Statutory And Regulatory Requirements For Process Validation
• Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable
requirement
• FDA regulations describing current good manufacturing practice (CGMP) for finished
pharmaceuticals are provided in 21 CFR
• The CGMP regulations require that manufacturing processes be designed and controlled to assure
that in-process materials and the finished product meet predetermined quality requirements and
do so consistently and reliably. This regulation requires manufacturers to design a process,
including operations and controls, which results in a product meeting these attributes.
• even well-designed processes must include in-process control procedures to assure final product
quality. In addition, the CGMP regulations regarding sampling set forth a number of requirements
for validation: samples must represent the batch under analysis; the sampling plan must result in
statistical confidence; and the batch must meet its predetermined specifications
• In addition to sampling requirements, the CGMP regulations also provide norms for establishing in-
process specifications as an aspect of process validation. In-process material should be controlled
to assure that the final drug product will meet its quality requirements. It also establishes the need
for manufacturers to analyze process performance and control batch-to-batch variability
• The information and data about product quality and manufacturing experience be periodically
reviewed to determine whether any changes to the established process are warranted. Ongoing
feedback about product quality and process performance is an essential feature of process
maintenance.
 Statutory And Regulatory Requirements For Process Validation
• the CGMP regulations require that facilities in which drugs are manufactured be of suitable size,
construction, and location to facilitate proper operations. Equipment must be of appropriate
design, adequate size, and suitably located to facilitate operations for its intended use. Automated,
mechanical, and electronic equipment must be calibrated, inspected, or checked according to a
written program designed to assure proper performance
• In summary, the CGMP regulations require that manufacturing processes be designed and
controlled to assure that in-process materials and the finished product meet predetermined quality
requirements and do so consistently and reliably.
• Keys for Successful Validation Include:
• Gaining knowledge from the product and process development
• Understanding sources of variation in the production process
• Determining the presence of and degree of variation
• Understanding the impact of variation on the process and end product
• Controlling variation in a manner aligned with Critical Quality Attributes (CQA) and the risk a
given attribute introduces to the process
 Designing of clinical studies
• What is the question
– The design of every clinical trial starts with a primary clinical research question. 
– Clarity and understanding of the research question can require much deliberation often
entailing a transition from a vague concept (e.g., “to see if the drug works” or “to look at the
neuro-biology of the drug”) to a particular hypothesis that can be tested or a quantity that can
be estimated using specific data collection instruments with a particular duration of therapy.
Secondary research questions may also be of interest but the trial design usually is
constructed to address the primary research question.
– There are two strategies for framing the research question. The most common is hypothesis
testing where researchers construct a null hypothesis (often “no effect” or “no difference”)
that is assumed to be true and evidence is sought to disprove it. An alternative hypothesis
(the statement that is desired to be claimed) is also constructed (often the presence of an
effect or difference between groups). Evidence is sought to support the alternative hypothesis.
The second strategy is estimation. For example a trial might be designed to estimate the
difference in response rates between two therapies with appropriate precision. Appropriate
precision might be measured by the width of a confidence interval of the difference between
the two response rates.
– Once the research question is well understood and associated hypotheses have been
constructed then the project team must evaluate the characteristics of the disease, the
therapies, the target population, and the measurement instruments.  The goal of design is to
construct the most efficient design within research constraints that will address the research
question while considering these characteristics.
 Designing of clinical studies
• Minimizing variation
– The larger the variation, the more difficult it is to identify treatment effects. Thus minimizing
variation is a fundamental element of clinical trial design. Minimizing variation can be
accomplished in several ways. One important method for reducing variation is to construct
consistent and uniform endpoint definitions. Ideally endpoints could be measured objectively
(e.g., via a laboratory test) however many endpoints are based on subjective evaluation. For
example, the diagnosis of neuropathy or dementia may be an end-point. However these
diagnoses are partly subjective. Variation in these diagnoses can be minimized with clear
definitions and consistent evaluations.
– A common design feature is the use of central labs for quantitating laboratory parameters to
eliminate between-lab variation or the use of central evaluators to eliminate between-
evaluator variation.
– Variation can also be reduced with standardization of the manner in which study participants
are treated and evaluated via training. For example, in studies that involve imaging, it is very
important to have an imaging protocol that standardizes the manner in which images are
collected to reduce added variation due to inconsistent patient positioning. Training modules
can be developed to instruct site personnel on the appropriate administration of evaluations.
 Designing of clinical studies
• Randomization and stratification
– Randomization is a powerful tool that helps control for bias in clinical trials. It essentially
eliminates the bias associated with treatment selection. Although randomization cannot
ensure between-treatment balance with respect to all participant characteristics, it does
ensure the expectation of balance. Importantly randomization ensures this expectation of
balance for all factors even if the factors are unknown or unmeasured.
– Trials commonly employ stratified randomization to ensure that treatment groups are
balanced with respect to confounding variables. In stratified randomization, separate
randomization schedules are prepared for each stratum. For example, gender is a potential
confounder for estimating the effects of interventions to treat or prevent stroke (e.g., a
between-group imbalance with respect to gender could distort the estimate of the
intervention effect). Thus trials investigating the effects of such interventions might employ
stratified randomization based on gender. For example, two randomization schedules may be
utilized; one for males and another for females. Stratified randomization ensures that the
number of male participants in each treatment group is similar and that the number of female
participants in each treatment group is similar. Stratification has a few limitations. First,
stratification can only be utilized for known and measurable confounders. Secondly, although
one can stratify on multiple variables, one has to be wary of over-stratification (i.e., too many
strata for the given sample size). The sample size must be large enough to enroll several
participants for each treatment from each stratum
 Designing of clinical studies
• Blinding
– Blinding is a fundamental tool in clinical trial design and a powerful method for preventing
and reducing bias. Blinding refers to keeping study participants, investigators, or assessors
unaware of the assigned intervention so that this knowledge will not affect their behavior,
noting that a change in behavior can be subtle, unnoticeable, and unintentional. When study
participants are blinded, they may be less likely to have biased psychological or physical
responses to intervention, less likely to use adjunct intervention, less likely to drop out of the
study, and more likely to adhere to the intervention. Blinding of study participants is
particularly important for patient reported outcomes (e.g., pain) since knowledge of
treatment assignment could affect their response. When trial investigators are blinded, they
may be less likely to transfer inclinations to study participants, less likely to differentially apply
adjunctive therapy, adjust a dose, withdraw study participants, or encourage participants to
continue participation. When assessors are blinded, they may be less likely to have biases
affect their outcome assessments
– Clinical trialists often use the terms “single-blind” to indicate blinding of study participants,
“double-blind” to indicate blinding of study participants and investigators, and “triple-blind”
to indicate blinding of participants, investigators, and the sponsor and assessors. Trials
without blinding are often referred to as “open-label”.
 Designing of clinical studies
• Placebos/Shams
–  placebo can be defined as an inert pill, injection, or other sham intervention that masks as an
active intervention in an effort to maintain blinding of treatment assignment. It is termed the
“sugar pill” and does not contain an active ingredient for treating the underlying disease or
syndrome but is used in clinical trials as a control to account for the natural history of disease
and for psychological effects. One disadvantage to the use of placebos is that sometimes they
can be costly to obtain.
– Although the placebo pill or injection has no activity for the disease being treated, it can
provide impressive treatment effects. This is especially true when the endpoint is subjective
(e.g., pain, depression, anxiety, or other patient reported outcomes).
 Designing of clinical studies
• Selection of a control group
– The selection of a control group is a critical decision in clinical trial design. The control group
provides data about what would have happened to participants if they were not treated or
had received a different intervention. Without a control group, researchers would be unable
to discriminate the effects caused by the investigational intervention from effects due to the
natural history of the disease, patient or clinician expectations, or the effects of other
interventions.
– There are three primary types of control groups: 1) historical controls, 2) placebo/sham
controls and 3) active controls. The selection of a control group depends on the research
question of interest. If it is desirable to show any effect, then placebo-controls are the most
credible and should be considered as a first option.
– Historical controls are obtained from studies that have already been conducted and are often
published in the medical literature. The data for such controls is external to the trial being
designed and will be compared with data collected in the trial being designed
– An active control is an active intervention that has often shown effectiveness to treat the
disease under study. Often an active control is selected because it is the standard of care
(SOC) treatment for the disease under study
 Designing of clinical studies
• Selection of a population and entry criteria
– In selecting a population to enroll into a trial, researchers must consider the target use of the
intervention since it will be desirable to generalize the results of the trial to the target
population. However researchers also select entry criteria to help ensure a high quality trial
and to address the specific objectives of the trial.
– The selection of a population can depend on the trial phase since different phases have
different objectives. Early phase trials tend to select populations that are more homogenous
since it is easier to reduce response variation and thus isolate effects. Later phase trials tend
to target more heterogeneous populations since it is desirable to have the results of such trials
to be generalizable to the population in which the intervention will be utilized in practice. It is
often desirable for this targeted patient population to be as large as possible to maximize the
impact of the intervention. Thus phase III trials tend to have more relaxed entry criteria that
are representative (both in demographics and underlying disease status) to the patient
population for which the intervention is targeted to treat.
– When constructing entry criteria, the safety of the study participant is paramount. Researcher
should consider the appropriateness of recruiting participants with various conditions into the
trial. The ability to accrue study participants can also affect the selection of entry criteria.
Although strict entry criteria may be scientifically desirable in some cases, studies with strict
entry criteria may be difficult to accrue particularly when the disease is rare or alternative
interventions or trials are available. Entry criteria may need to be relaxed so that enrollment
can be completed within a reasonable time frame.
 Designing of clinical studies
• Sample size
– Sample size is an important element of trial design because too large of a sample size is
wasteful of resources but too small of a sample size could result in inconclusive results.
– Calculation of the sample size requires a clearly defined objective.
– The analyses to address the objective must then be envisioned via a hypothesis to be tested
or a quantity to be estimated.
– The sample size is then based on the planned analyses
 Other important concepts in designing of clinical studies
• Case Series: Case series are studies that describe in detail a group of subjects who share common
characteristics and/or have received similar interventions.
• Observational Studies: Observational studies provide a mechanism for clarifying the epidemiology
and risk factors/exposures that place populations at risk for disease. Observational studies assist in
identifying clinical outcomes that might aid in predicting future disease. This type of study allows
researchers to draw conclusions about responses to variables; they allow for associations but not
causation.
• Cohort Studies: Longitudinal studies that are designed to follow a group of subjects over time. A
cohort is a group of subjects that share a common characteristic, such as age, exposure to an
environmental agent, or risk for a specific disease. Cohort studies often test hypotheses aimed to
identify associations between a given characteristic and an outcome. Cohort studies may be
retrospective (looking back in time) or prospective (looking forward in time).
– Retrospective Cohort Study: A study population is defined and the medical history is reviewed to identify associations
between exposures and a given outcome. This type of study is also known as a historical cohort study. Retrospective cohort
studies often serve as the background for development of an interventional trial. Example: Chart review of pediatric subjects
with a known diagnosis of late-onset congenital adrenal hyperplasia to determine linear growth patterns prior to diagnosis.
II. Prospective Cohort Study: A defined study cohort is followed forward in time to determine how factors/exposures affect a
given outcome.
– Prospective studies can help identify risk factors for disease because data is collected at set time intervals. Risk to these
studies is loss to follow-up and length of time needed to determine associations. Example of a prospective cohort study is
the Bogalusa Heart Study. This study began in 1973 to determine the natural history of cardiovascular disease in a group of
12,000 children from Bogalusa, LA
 Other important concepts in designing of clinical studies
• Case/Control: Observational study in which likelihood of exposure is compared between representative
groups with (case) and without (control) a disease. Data can be conducted either retrospectively or
prospectively. These studies can identify associations between a disease and risk factors or disease
outcomes. Case-control studies generally require fewer subjects and are less expensive than cohort
studies, and they can be particularly useful in epidemiologic investigations to identify risk factors for
disease. A case-control design may also be appropriate for studying very rare diseases/outcomes that
would not be encountered in sufficient numbers using a prospective cohort design.
• Cross-Sectional Studies: This type of cohort study takes a “snap-shot” of a given population at one point in
time. In a cross-sectional study, a cohort of interest is identified and a set of factors related to an outcome
is explored. In some cases, discrete biochemical data is obtained to strengthen associations. Cross-
sectional studies can provide prevalence data for disease, as well as rates of risk exposures and
associations between risk factors and an outcome of interest
• Intervention Studies: Intervention studies test the impact of an intervention on a given outcome. In an
interventional study, a variable is manipulated, and the effect of that manipulation on a defined outcome is
measured. Pilot Studies: Pilot studies are small, feasibility studies that are usually performed to test
hypotheses in preparation for a larger interventional clinical trial. Pilot studies allow investigators to test
experimental design, obtain preliminary data for power analysis (see below), and provide information
about subject recruitment and study management before investing resources to a larger study.
• Randomized Controlled Trials: Randomized controlled trials (RCTs) are intervention studies in which a
group of subjects with similar characteristics are randomized to receive one of several defined
interventions. The goal is to determine quantitatively the effect of an intervention on a defined outcome.
RCTs are powerful tools to test a hypothesis. These studies are often the basis for evidence-based medicine
practice, and are considered the gold-standard in clinical research. Pilot studies may provide the
groundwork for the development of a RCT
 Other important concepts in designing of clinical studies
• Placebo-Controlled: In placebo-controlled studies, subjects are randomized to receive either
placebo (sugar-pill, inactive excipients) or the active intervention. Placebo controlled trials may be
challenging to perform, particularly if the intervention involves an injection or use of a device. In
addition, in cases where an established therapy is already considered to be standard of care,
placebo-controlled trials may be considered unethical if the usual treatment is withdrawn while
the subject is enrolled in the study. In some cases, the placebo arm of the study is actually defined
as a non-intervention arm.
• Active Comparator: In some RCTs, subjects are randomized to an active comparator arm which is
compared to an experimental intervention arm. An active comparator is used when it would be
unethical or impractical to randomize subjects to placebo or nonintervention. Active comparator
trials are powerful methods to determine if a new therapy is non-inferior or superior to current
standard of care treatments.
• Cross-Over Design: In a RCT, there are situations when subjects cross-over into another
intervention. For instance, all subjects randomized to active comparator may be crossed-over to
receive the experimental agent after a set time period, while all subjects receiving the
experimental agent will cross-over to the active comparator. The advantages to this design are that
each subject serves as his/her own control, and the number of subjects needed to answer a clinical
question may be less. Thus, the investigator can analyze the data within and between subjects. A
concern with this design is that it is important to make sure that subjects are the same at the time
of the cross-over as they were at the initiation of the study. This design must also take into
consideration the “order-effect” which states that the order of interventions may influence the
outcome
SAD and MAD: Sisngle ascending dose and multiple ascending dose
*TdP: life-threatening arrhythmia torsades de pointes (TdP). translated as "twisting of
peaks"), is a specific type of abnormal heart rhythm that can lead to sudden cardiac death.
 New Drug Application (NDA)
• For decades, the regulation and control of new drugs in the United States has been based on the
New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA
before U.S. commercialization.  The NDA application is the vehicle through which drug sponsors
formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. 
The data gathered during the animal studies and human clinical trials of an Investigational New
Drug (IND) become part of the NDA.
• The goals of the NDA are to provide enough information to permit FDA reviewer to reach the
following key decisions:
– Whether the drug is safe and effective in its proposed use(s), and whether the benefits of the
drug outweigh the risks.
– Whether the drug's proposed labeling (package insert) is appropriate, and what it should
contain.
– Whether the methods used in manufacturing the drug and the controls used to maintain the
drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.
• The documentation required in an NDA is supposed to tell the drug's whole story, including what
happened during the clinical tests, what the ingredients of the drug are, the results of the animal
studies, how the drug behaves in the body, and how it is manufactured, processed and packaged.
• When an NDA is submitted, the FDA has 60 days to decide whether to file it for review, or reject it if
some required information is missing. The goal of the FDA’s Center for Drug Evaluation and
Research (CDER) is to review and act on at least 90% of NDAs for standard drugs within 10 months
after the applications are received, and six months for priority drugs.
 New Drug Application (NDA)
• CDER classifies New Drug Applications with a code from 1 through 7 that reflects the type of drug
being submitted and its intended uses. For example, Code 1 stands for a “New Molecular Entity,”
while Code 4 indicates a new combination of two or more drugs. Drugs also receive a code
indicating whether they will receive Standard review or Priority review, the latter being reserved
for drugs that represent significant advances over existing treatments.
• Once the CDER review of an NDA is completed, it issues one of three possible action letters to the
sponsor of the new drug –
• Approval Letter: this states that the drug is approved.
• Approvable Letter: indicates that the drug can be ultimately approved, but lists minor deficiencies
that need to be rectified; it often asks for labeling changes and sometimes for sponsor
commitment to undertake post-marketing studies.
• Not Approvable Letter – lists deficiencies in the application and the reasons why the drug cannot
be approved.
• Once a company reaches the NDA stage, the probability of the drug receiving FDA approval and
being marketed in the U.S. exceeds 80%. Filing of an NDA typically does not result in a substantial
increase in the share price of the sponsor company, as most of the stock appreciation is likely to
have occurred as the investigational drug progressed through successive phases of earlier clinical
trials.
 New Drug Application (NDA) classification codes
• The NDA classification code provides a way of categorizing new drug applications. The code
evolved from both a management and a regulatory need to identify and group product applications
based on certain characteristics, including their relationships to products already approved or
marketed in the United States.
• Type 1 — New Molecular Entity: A Type 1 NDA is for a drug product that contains an NME. An NME
is an active ingredient that contains no active moiety that has been previously approved by the
Agency . A pure enantiomer or a racemic mixture is an NME only when neither has been previously
approved or marketed
• A Type 2 NDA is for a drug product that contains a new active ingredient, but not an NME. A new
active ingredient includes those products whose active moiety has been previously approved or
marketed in the United States, but whose particular ester, salt, or noncovalent derivative of the
unmodified parent molecule has not been approved by the Agency or marketed in the United
States, either alone, or as part of a combination product. Similarly, if any ester, salt, or noncovalent
derivative has been marketed first, the unmodified parent molecule would also be considered a
new active ingredient, but not an NME. The indication for the drug product does not need to be
the same as that of the already marketed product containing the same active moiety
• A Type 3 NDA is for a new dosage form of an active ingredient that has been approved or marketed
in the United States by the same or another applicant but in a different dosage form
• A Type 4 NDA is for a new drug-drug combination of two or more active ingredients. An application
for a new drug-drug combination product may have more than one classification code if at least
one component of the combination is an NME or a new active ingredient. The new product may be
a physical or chemical (e.g., covalent ester or noncovalent derivative) combination of two or more
active moieties.
 New Drug Application (NDA) classification codes
• Type 5 — New Formulation or Other Differences (e.g., new indication, new applicant, new
manufacturer) . The product may involve changes in inactive ingredients that require either
bioequivalence studies or clinical studies for approval and is submitted as an original NDA rather than as
a supplement by the applicant of the approved product. . The product may be a duplicate of a drug
product by another applicant (same active ingredient, same dosage form, same or different indication, or
same combination). The product may contain an active ingredient or active moiety that has been
previously approved or marketed in the United States only as part of a combination
• Type 6 — New Indication or Claim, Same Applicant: This NDA classification code is no longer used and is
replaced with Type 9 and Type 10.
• A Type 7 NDA is for a drug product that contains an active moiety that has not been previously approved
in an application, but has been marketed in the United States
• A Type 8 NDA is for a drug product intended for over-the-counter (OTC) marketing that contains an active
ingredient that has been approved previously or marketed in the United States only for dispensing by
prescription (OTC switch). A Type 8 NDA may provide for a different dosing regimen, different strength,
different dosage form, or different indication from the product approved previously for prescription sale.
• A Type 9 NDA is for a new indication or claim for a drug product that is currently being reviewed under a
different NDA (the ‟parent NDA”), and the applicant does not intend to market this drug product under
the Type 9 NDA after approval.
• A Type 10 NDA is for a drug product that is a duplicate of a drug product that is the subject of either a
pending or approved NDA, and the applicant intends to market the drug product under this separate
Type 10 NDA after approval. A Type 10 NDA is normally for a drug product that has a new indication or
claim, and it may have labeling and/or a proprietary name that is distinct from that of the original NDA.
 Approval Process
• FDA approval of a drug means that data on the drug’s effects have been reviewed by CDER, and the
drug is determined to provide benefits that outweigh its known and potential risks for the intended
population. The drug approval process takes place within a structured framework that includes:
• Analysis of the target condition and available treatments—FDA reviewers analyze the condition
or illness for which the drug is intended and evaluate the current treatment landscape, which
provide the context for weighing the drug’s risks and benefits. For example, a drug intended to
treat patients with a life-threatening disease for which no other therapy exists may be considered
to have benefits that outweigh the risks even if those risks would be considered unacceptable for a
condition that is not life threatening.
• Assessment of benefits and risks from clinical data—FDA reviewers evaluate clinical benefit and
risk information submitted by the drug maker, taking into account any uncertainties that may result
from imperfect or incomplete data. Generally, the agency expects that the drug maker will submit
results from two well-designed clinical trials, to be sure that the findings from the first trial are not
the result of chance or bias. In certain cases, especially if the disease is rare and multiple trials may
not be feasible, convincing evidence from one clinical trial may be enough. Evidence that the drug
will benefit the target population should outweigh any risks and uncertainties.
 Approval Process
• Strategies for managing risks—All drugs have risks. Risk management strategies include an FDA-
approved drug label, which clearly describes the drug’s benefits and risks, and how the risks can be
detected and managed. Sometimes, more effort is needed to manage risks. In these cases, a drug
maker may need to implement a Risk Management and Mitigation Strategy (REMS).
• Although many of the FDA’s risk-benefit assessments and decisions are straightforward, sometimes
the benefits and risks are uncertain and may be difficult to interpret or predict. The agency and the
drug maker may reach different conclusions after analyzing the same data, or there may be
differences of opinion among members of the FDA’s review team. As a science-led organization,
FDA uses the best scientific and technological information available to make decisions through a
deliberative process
• Accelerated Approval: In some cases, the approval of a new drug is expedited. Accelerated
Approval can be applied to promising therapies that treat a serious or life-threatening condition
and provide therapeutic benefit over available therapies. This approach allows for the approval of a
drug that demonstrates an effect on a “surrogate endpoint” that is reasonably likely to predict
clinical benefit, or on a clinical endpoint that occurs earlier but may not be as robust as the
standard endpoint used for approval. This approval pathway is especially useful when the drug is
meant to treat a disease whose course is long, and an extended period of time is needed to
measure its effect. After the drug enters the market, the drug maker is required to conduct post-
marketing clinical trials to verify and describe the drug’s benefit. If further trials fail to verify the
predicted clinical benefit, FDA may withdraw approval.
 Approval Process

• The agency also employs several approaches to encourage the development of certain drugs,
especially drugs that may represent the first available treatment for an illness, or ones that have a
significant benefit over existing drugs. These approaches, or designations, are meant to address
specific needs, and a new drug application may receive more than one designation, if applicable.
Each designation helps ensure that therapies for serious conditions are made available to patients
as soon as reviewers can conclude that their benefits justify their risks.
• Fast Track is a process designed to facilitate the development and advance the review of drugs that
treat serious conditions, and fill an unmet medical need, based on promising animal or human
data. Fast tracking can get important new drugs to the patient earlier. The drug company must
request the Fast Track process.
• Breakthrough Therapy designation expedites the development and review of drugs that are
intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may
demonstrate substantial improvement over available therapy. A drug with Breakthrough Therapy
designation is also eligible for the Fast Track process. The drug company must request a
Breakthrough Therapy designation.
• Priority Review means that FDA aims to take action on an application within six months, compared
to 10 months under standard review. A Priority Review designation directs attention and resources
to evaluate drugs that would significantly improve the treatment, diagnosis, or prevention of
serious conditions.
 Drug Scheduling

• Drugs, substances, and certain chemicals used to make drugs are classified into five (5) distinct
categories or schedules depending upon the drug’s acceptable medical use and the drug’s abuse or
dependency potential.
• The abuse rate is a determinate factor in the scheduling of the drug; for example, Schedule I drugs
have a high potential for abuse and the potential to create severe psychological and/or physical
dependence.
• As the drug schedule changes-- Schedule II, Schedule III, etc., so does the abuse potential--
Schedule V drugs represents the least potential for abuse.
• A Listing of drugs and their schedule are located at Controlled Substance Act (CSA) Scheduling or
CSA Scheduling by Alphabetical Order.
• These lists describes the basic or parent chemical and do not necessarily describe the salts,
isomers and salts of isomers, esters, ethers and derivatives which may also be classified as
controlled substances.
• Schedule I
• Schedule I drugs, substances, or chemicals are defined as drugs with no currently accepted medical
use and a high potential for abuse. Some examples of Schedule I drugs are: heroin, lysergic acid
diethylamide (LSD), marijuana (cannabis), 3,4-methylenedioxymethamphetamine (ecstasy),
methaqualone, and peyote
 Drug Scheduling
• Schedule II
• Schedule II drugs, substances, or chemicals are defined as drugs with a high potential for abuse,
with use potentially leading to severe psychological or physical dependence. These drugs are also
considered dangerous. Some examples of Schedule II drugs are: Combination products with less
than 15 milligrams of hydrocodone per dosage unit (Vicodin), cocaine, methamphetamine,
methadone, hydromorphone (Dilaudid), meperidine (Demerol), oxycodone (OxyContin), fentanyl,
Dexedrine, Adderall, and Ritalin
• Schedule III
• Schedule III drugs, substances, or chemicals are defined as drugs with a moderate to low potential
for physical and psychological dependence. Schedule III drugs abuse potential is less than Schedule
I and Schedule II drugs but more than Schedule IV. Some examples of Schedule III drugs are:
Products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine),
ketamine, anabolic steroids, testosterone
• Schedule IV
• Schedule IV drugs, substances, or chemicals are defined as drugs with a low potential for abuse
and low risk of dependence. Some examples of Schedule IV drugs are: Xanax, Soma, Darvon,
Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol
• Schedule V
• Schedule V drugs, substances, or chemicals are defined as drugs with lower potential for abuse
than Schedule IV and consist of preparations containing limited quantities of certain narcotics.
Schedule V drugs are generally used for antidiarrheal, antitussive, and analgesic purposes. Some
examples of Schedule V drugs are: cough preparations with less than 200 milligrams of codeine or
per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin
 Drug Scheduling
• In India, The Drugs and Cosmetics Rules, 1945 contains provisions for classification of drugs under
given schedules and there are guidelines for the storage, sale, display and prescription of each
schedule..
• The notable Schedules and their summary are given below
– Schedule G: Most of these drugs are hormonal preparations. The drug label must display the
text "Caution: It is dangerous to take this preparation except under medical
supervision" prominently. Examples of substances under this
schedule: Testolactone, Hydroxyurea, Carbutamide, Primidone etc.[
– Schedule H: The drug label must display the texts "Rx" and "Schedule H drug. Warning : To be
sold by retail on the prescription of a Registered Medical practitioner only" prominently. It can
only be supplied to licensed parties. It cannot be sold without a prescription and only the
amount specified in the prescription should be sold. The time and date of prescription must
be noted.
Examples: androgenic, anabolic, oestrogenic and progestational substances; Alprazolam (Xana
x), Hepatitis B vaccine, Ibuprofen, Vasopressin etc
– Schedule X: All the regulations of Schedule H apply. The retailer must keep a copy of the
prescription for two years. The drugs must be kept under lock and key.
Examples: Secobarbital, Glutethimide etc
– Schedule J: Contains a list of various diseases and conditions that cannot be treated under any
drug currently in market. No drug may legally claim to treat these diseases
 Post approval surveillance
• A vital part of CDER's mission is to monitor the safety and effectiveness of drugs that are currently
available to the American people.  To meet this goal, FDA has in place postmarketing programs that
monitor marketed human medical products for unexpected adverse events. These programs alert
the Agency to potential threats to the public health.  Agency experts then identify the need for
preventive actions, such as changes in product labeling information and, rarely, re-evaluation of an
approval decision. 
• The FDA Adverse Event Reporting System (FAERS) is a computerized information database designed
to support the FDA's post-marketing safety surveillance program for all approved drug and
therapeutic biologic products. The ultimate goal of FAERS is to improve the public health by
providing the best available tools for storing and analyzing safety reports. The reports in FAERS are
evaluated by a multidisciplinary staff safety evaluators, epidemiologists and other scientists in the
Center for Drug Evaluation and Research's (CDER) Office of Surveillance and Epidemiology to detect
safety signals and to monitor drug safety.
• After a drug is approved and marketed, the FDA uses different mechanisms to assure that firms 1)
adhere to the terms and conditions of approval described in the application and 2) that the drug is
manufactured in a consistent and controlled manner. This is done by periodic, unannounced
inspections of drug production and control facilities by FDA's field investigators and analysts.
• Manufacturers of prescription medical products are required by regulation to submit adverse event
reports to the FDA. The MedWatch site provides information on mandatory reporting by
manufacturers. In addition, drug manufacturers must submit either error and accident reports or
drug quality reports when deviation from current good manufacturing practice regulations occur.