B.pharmacy 8th semester

1. PHARMACEUTICAL
REGULATORY SCIENCE
UNIT I
CHAPTER 1

2. NEW DRUG DISCOVERY AND
DEVELOPMENT

3. INTRODUCTION
Drug discovery is a process aimed at identifying a compound therapeutically
useful in remedial and treating diseases. The process of drug discovery
involves the identification of candidates, synthesis, characterization,
screening, and assays for therapeutic efficacy. Researchers constantly put
their efforts to discover new drugs through new insights into a disease
process that allow them to design a product to overcome the effects of the
disease. Several tests are conducted on a compound to find possible useful
effects against number of diseases. In addition, existing treatments that have
unanticipated effects can also be explored.

4. History of Drug Discovery
(a)Early Drug Discovery:
Drug discovery has a long history that dates back to the early days of human
civilization. In those times, drugs were used for physical remedies and also
were associated with some religious and spiritual healing. Religious chiefs were
the major administrators of drugs. The early drugs were mainly obtained from
plants, animals, and minerals. These drugs were discovered through trial and
error experimentation and observation of human and animal responses upon
the use of such product.

5. (b) Middle Age Drug Discovery:
The middle age, from around 400 to 1500 AD, plagues scourged many parts
of Europe. Diseases such as bubonic plague, leprosy, smallpox, tuberculosis,
and scabies were beyond control and many people gave away lives to these
diseases. There are few references to herbs used to treat diseases in the
Bible. Many churches preserved the transcription of Greek medical
manuscripts and treatises. These transcripts helped to develop knowledge in
ancient times to be continued in a later period. Arabians mainly being traders
with many regions learned and extended medical knowledge.

6. (C) Current Drug Discovery:
The middle-age period was the foundation for scientific thinking in medicinal
preparations and medical treatments. There were many advances made in
anatomy, physiology, surgery, and medical treatments including public health
care, hygiene, and sanitation. Until the late 18th century, most drugs were
based on herbs or extracted ingredients from plant sources. Although advances
were made in the 1800s, there were only a few drugs available for treating
diseases at the beginning of the 1900s. Some of these were digitalis extracted
from a plant called foxglove which stimulates the cardiac muscles, and was
used to treat cardiac conditions, quinine derived from the bark of the cinchona
tree, and used to treat malaria, ipecacuanha extracted from the bark or root of
the cephalic plant and used to treat dysentery, acetylsalicylic acid extracted
from the bark of willow tree and used for the treatment of fever, mercury was
used to treat syphilis, etc.

7. (d) Naming of New Drugs:
Every drug has its proprietary or brand name. During the R&D stage, a new
pharmaceutical compound is given an International Non-proprietary Name
(INN) or generic name. Each INN is unique which is recognized worldwide and
is public property. Non-proprietary names are intended for use in
pharmacopeias, labeling, product information, and advertising and other
promotional material, drug regulation, and scientific literature. Non-
proprietary name is the basis for product names, for example for generics.
Their use is normally required by national or, as in the case of the EU, by
international legislation. Names which are given the status of an INN are
selected by the WHO on the advice of experts from the WHO Expert Advisory
Panel on the International Pharmacopoeia and pharmaceutical preparations.

8. STAGES OF DRUG DISCOVERY
Drug discovery effort addresses a biological target that has shown to play a
role in the development of the disease or starts from a molecule with
interesting biological activities. The drug discovery process (Fig. 1.1) involves
the identification of candidate drugs, its synthesis, characterization,
screening, and assays for therapeutic efficacy.

10. DRUG DEVELOPMENT PROCESS
Not every compound that is tested in the laboratory is marketed but before it
is marketed; it has to undergo several stages of development called drug
development. The drug development process converts potential drug
candidates through regulatory approval to the marketing. In this process, the
new drug candidate adheres to high standards in the conduct, analysis, and
interpretation of preclinical and clinical studies for its regulatory approval. In
fact, drug development is an uncertain pharmaceutical activity with risks

11. Stages of Development of a New Drug
(a) Preclinical Stage: The preclinical stage comprises studies on animals to find
out various parameters for a potential drug candidate under the process of
development. During this stage, a sponsor (innovator) evaluates the drug's
toxic and pharmacological effects through in vitro testing and in vivo laboratory
animal testing. Genotoxicity screening as well as investigation of drug
absorption and metabolism, the toxicity of the candidate drug's metabolites,
and the rate at which the candidate drug and its metabolites are excreted from
the body are conducted. At the preclinical stage, the U.S. FDA's minimum
requirement is that a sponsor should develop a pharmacological profile of the
drug; determine its acute toxicity in at least two species of animals and conduct
short-term toxicity studies ranging from 2 weeks to 3 months, depending on
the proposed duration of use of the candidate drug in the proposed clinical
studies.

12. (b) Clinical Stage: Clinical stage development of potential drug candidates
comprises of pharmaceutical clinical trials which are commonly conducted in 4
phases.
Phase-0: This is an exploratory phase of a clinical trial that expedite the
development of a promising drug by establishing early on whether the agent
behaves in human subjects as was anticipated from preclinical studies.
Phase-I: Studies in Phase-I are carried out in a small number of healthy
volunteers, usually 20 to 100 with the disease or condition and the study
requires several months.

13. Phase-II: This phase includes the early controlled clinical studies conducted to
obtain some preliminary data on the effectiveness (efficacy) of the potential drug
for a particular indication or indications in patients with the disease or condition.
Testing in this phase help to determine the common short-term side effects and
risks associated with the drug under testing. These studies are typically well-
controlled, closely monitored, and performed on larger groups of patients, usually
involving 20-300.

14. Phase-III: Phase 3 studies are expanded, controlled, and uncontrolled trials.
They are performed following preliminary evidence of the effectiveness of the
potential drug at Phase-II. The purpose of the study at this phase is to gather
additional information about the effectiveness and monitoring of adverse
reactions. The results of studies at this phase provide an adequate basis to
extrapolate them to the general population and transmitting that information in
the physician labeling. Phase 3 studies usually include several hundred to
several thousand people, usually 300 to 3,000 who have the disease or
condition.

15. Phase-IV: This phase is also known as Post Marketing Surveillance (PMS) and is
carried out once the candidate drug is approved as a drug and marketed as a
medicinal product. This phase aims to find out the drug safety profile in a large
patient pool across the world and to establish its safety profile. It is estimated
that the success rate of drugs making to market from the laboratory is very
less. The post-launch safety monitoring helps to detect rare or long-term
adverse effects of the drug over a large patient population and time scale than
was possible during a clinical trial. Usually, several thousand volunteers who
have the disease or condition are involved in this phase of the trial.

16. Time Required For Developing A New Drug: Drug development is a very slow
process because a candidate drug is examined at e. standards Manufacturers
ed stage of development by the regulatory authorities in various countries
before it is launched into the market. According to PhRMA (Pharmaceutical
Research and America, A pharma industry trade group of America), it may
range between 12 to 15 of to develop a new drug. The reasons for the
slowness of drug development includes almost six-and-a-half years of
discovery, preclinical testing, and toxicity studies; about 1.5 years in Phase-I
trials; 2 years in Phase-II trials; about 3.5 years in Phase-III trials and about 1.5
years of regulatory authority review and approval.

17. schematic representation of drug developing process

18. Cost of Developing New Drug: Drug development requires a huge
investment from pharmaceutical companies. It is estimated, according to
various sources that the cost of developing a single new drug including
commercialization varies from US$800 million to US$1.7 billion.

19. (C) Regulatory Approval:
1. IND: Once the candidate drug is tested in animals (preclinical testing), a
sponsor files IND with regulatory authority for getting approval for testing it in
humans. The IND application includes information such as; results of previous
experiments; how, where, and by whom the new studies will be conducted;
the chemical structure of the candidate drug; how it works in the body
(mechanism of action); any toxic effects found in the animal studies; and how
it is manufactured.

20. The IND must be reviewed and approved by the Institutional Review Board
(IRB) where the studies are to be conducted, and progress reports on clinical
trials are required to be submitted to regulatory authority periodically. IND
application contains information such as:
(i) Animal pharmacology and toxicology studies.
(ii) Manufacturing information of candidate drug including; manufacturer,
composition, stability, and controls.
(iii) Clinical protocols and investigator information.

21. 2. NDA: The NDA application is the medium through which new drug sponsors
formally propose that the regulatory authority approve this drug for sale and
marketing in the country of approval. The goals of the NDA are to provide enough
information to permit regulatory reviewers to reach the following key decisions:
(i) Whether the new drug is safe and effective in its proposed use(s), and whether
the benefits of the drug outweigh the risks.
(ii) Whether the proposed labeling (package insert) of the new drug is
appropriate, and what it should contain.
(iii) Whether the methods used in manufacturing the new drug and the controls
used to maintain its quality are adequate to preserve its identity, strength,
quality, and purity.

22. PRECLINICAL RESEARCH
The development of a new drug begins with the synthesis and purification of
the new drugs . Pre chemical moiety or the screening of existing compounds
for potential use as clinical research aims to determine the potential to cause
any toxicity or to determine whether the drug is reasonably safe for potential
use in humans , and sufficiently effective against a disease target in chemical
tests or animal models . The two types of preclinical research are in vitro and
in vivo . FDA requires researchers to follow Good Laboratory are found in 21
CFR Practices ( GLP ) for preclinical laboratory studies .

23. NON-CLINICAL ACTIVITIES
The non-clinical (or pre-clinical) development primarily aims to identify
potential drugs for the greatest possibility of success, assess its safety, and
build a solid scientific base before shift it into the clinical development phase.
At this stage, the candidate drug is supposed to meet non-medical objectives,
including defining the intellectual property right (IPR) and making enough
medicinal products available for clinical trials. The non-clinical phase is
complex and regulatory-driven. In this phase pharmacodynamics,
pharmacokinetics, and toxicology data of the candidate drug are identified
before its use in humans. Also, the data from non-clinical studies are used to
refine, consolidate, and add information to update the safety profile of the
candidate drug at the time of registration, and during the life-cycle of the
approved medicinal product.

24. CLINICAL RESEARCH
Preclinical research answers basic questions about a drug's safety and is not a
substitute for how a drug will interact with the human body. This is determined
from clinical research which refers to studies, or trials, that are done in a human
volunteer. During the design of the clinical study, sponsors consider what to
accomplish at the end of each clinical research phases and begin the IND process
before clinical research begins. Amongst the various costs involving stages in
drug development, clinical trials for IND are the biggest cost associated phase.
Unfortunately, with this huge investment, about 90% of all INDs fail at some
phase in clinical trials. This is mainly attributable to the fact that most IND R&D is
done in animal models and cell cultures which in a real sense is different from
the human body. Thus, translation of efficacy, clinical safety, and toxicology data
to humans is not assured.

25. 1. Designing Clinical Trials
Clinical trials are designed to answer specific research questions related to a
medical product. This research follows a specific study plan called a protocol
that is developed by the researcher or manufacturer. Before a clinical trial
begins, researchers review prior information about the candidate drug to
develop objectives and research questions to answer. Some of the major
questions are:
1. Who qualifies to participate in a clinical trial (selection criteria)?
2. How many volunteers will be part of the study?
3. How long the study will last?
4. Whether there will be a control group and other ways to limit research bias?

26. 2. IND Process
Once the clinical trials are completed successfully, the whole of the information
about the candidate drug is compiled into an IND application and submitted to
the relevant competent authority. For example, FDA in the US, the European
Medicines Agency (EMA) in Europe, and Drug Controller General of India (DCGI)
in India, etc. The competent authority reviews the IND application and if
additional information is required to them it may be sought from the applicant
or obtained through discussions held with the applicant before making any
decision. The regulator upon assessing the scientific data submitted in the IND
application, either allow it to be marketed or deny approval to the applicant.

27. 3. IND Review Team
The IND review team consists of a group of specialists in different scientific fields.
Each member of this team has different responsibilities:
1. Project manager: The project manager is the head of the team who
coordinates the team's activities throughout the review process, and is the
primary contact for the sponsor.
2. Medical officer: Medical officer reviews all clinical study information and data
before, during, and after the trial is complete.
3. Statistician: Statisticians interprets clinical trial designs and data, and works
closely with the medical officer to evaluate protocols and safety and efficacy
data.

28. 4. Pharmacologist: Pharmacologist reviews preclinical studies.
5. Pharmakineticist: Pharmakineticist focuses on the drug's absorption,
distribution, metabolism, and excretion processes. Interprets blood-level data at
different time intervals from clinical trials to assess drug dosages and
administration schedules.
6. Chemist: Chemist evaluates a drug's chemical compounds, analyzes how a drug
was made and its stability, quality control, continuity, the presence of impurities,
etc.
7. Microbiologist: Microbiologist reviews the data submitted, if the product is an
antimicrobial product, to assess response across different classes of microbes.

29. 4. IND Approval
The regulatory authority has a specific period to review the original IND
submission. For example, U.S. FDA review team has 30 days. The process protects
volunteers who participate in clinical trails from unreasonable and significant
risk. Regulatory authority responds to IND applications in one of two ways:
1. Approval to begin clinical trials.
2. Clinical hold to delay or stop the investigation.

30. 5. FDA Drug Review
If a drug sponsor has evidence from its early tests and preclinical and clinical
research that a drug is safe and effective for its intended use, the company
can file an application to market the drug. The U.S. FDA review team
thoroughly examines all submitted data on the drug and decides to approve
or not to approve it.

31. The sponsor must include reports on all, studies data, and analyses. Along with
clinical results, the sponsor must include:
1. Proposed labeling.
2. Safety updates
3. Drug abuse information
4. Patent information.
5. Any data studies that may have been conducted outside the United States.
6. Institutional review board compliance information.
7. Directions for use

32. 6. Regulatory Approval
In cases where the regulator found that the new drug is safe and effective for its
intended use, it is then necessary to work with the applicant to develop and
refine prescribing information. This is referred to as labeling. Labeling accurately
and objectively describes the basis for approval and how best to use the drug.
Often, remaining issues are also resolved prior to the approval of the drug for
marketing. In some cases, the regulator requires the sponsor to answer
questions based on existing data. While in other cases, they require additional
studies to be conducted to make the decision. In such. a situation, the sponsor
can decide whether or not to continue with further development. If a sponsor
disagrees with the regulator decision, they can make a formal appeal through a
mechanism in place.

33. 7. Post-Market Drug Safety Monitoring
Clinical trials provide important information on a drug's efficacy and Safety, but
it ;impractical to have complete information about the safety of a drug at the
time of approval. Even though the precise steps are taken during drug
development, limitations exist. The true and actual picture of a product's safety
is observed over the months and even years of product in the marketplace. Post-
market drug safety monitoring (post-market surveillance)is also called Phase-IV
trials of the drug. These studies are conducted to continually assess the safety of
the drug in the marketplace. This includes reporting and investigation of the
incidence and severity of rare adverse reactions, cost-effectiveness analyses,
comparative trials, and quality of life studies.

34. Innovator drug product
Innovator product is the more appropriate term for newly developed drug
products. The innovator product is generally that which is first authorized for
marketing which normally isa patented product. When a drug product has been
available for many years, it may not be possible to identify an Innovator drug
product. Companies who develop new medicines invest 10% to 20% of their
revenue on R & D. The innovation process may start with promising compounds,
but out of 10,000 compounds tested, usually, one compound is finally a proved as
a drug by the regulatory authorities. To develop a new drug product, certain
companies put a tremendous amount of effort into research to find a medication
that will be effective and safe for use. An innovator (pioneer) drug is the first drug
product| that contains its specific active ingredient to receive approval for use. It
is usually that for which efficacy, safety, and quality have been fully established.

35. CONCEPT OF GENERIC:
On September 24, 1984, in the 98th U.S. Congress, the Act named ‘The Drug Price
Competition and Patent Term Restoration Act’ was passed, also known as the Hat
Waxman Act. The objective of this act was to encourage the manufacturing of
generic drugs by the pharmaceutical industries and to establish the modern
system of government generic drug regulation in the USA. The requirement for
this was to submit an Abbreviated a .Drug Application (ANDA) by the
pharmaceutical companies to tie regulatory authorities for getting the approval
to. market a generic drug. ANDA process does not require manufacturer to carry
out repeat testing of generics in animals which is costly and time ;consuming, as
their branded versions have already been tested and approved for safety a
effectiveness. Generics are formulated, developed, and manufactured by other
companies when patent and other exclusivity rights of the innovator have
expired.

36. 1. approval process of generic Drug Product
The manufacturer of an innovator product can become a manufacturer of a
generic version of the drug, once the patent for the drug has expired and it
becomes open to generic competition. This allows the innovator to continue to
recover the cost of investment from first introducing the product to the market.
To seek marketing approval, a generic drug must meet the same batch
requirements for identity, strength, purity, and quality and be therapeutically
equivalent to the branded product. Additionally, the drug must be
manufactured according to the same Gmp. For the generic drug to be
therapeutically equivalent, it must be pharmaceutically equivalent as well as
bioequivalent. Pharmaceutical equivalence means that the active ingredient(s),
dose form, route of administration, and strength are the same for both the
branded product and the generic product.

37. 2. Standards for Generic Drug Products
The Hatch-Waxman Act 1984 allowed for an abbreviated system for approval of
generic copies of all drugs approved after 1962, meaning that pre-clinical and
clinical testing did not have to be repeated for generics. This legislation was to
ensure that generic medicines would be less expensive than the equivalent
innovator drug product because generic drug product manufacturers did not
need to repeat discovery, pre-clinical and clinical studies. Drug manufacturers
can submit an ANDA for approval to market a generic drug that is the same as
(or bioequivalent to) the branded version.

38. 3. Effectiveness of Generic Drug Products
Any generic drug product must perform the same way in the body as the
branded drug Product and thus this standard applies to all generic drug
products. A generic drug product is the same as a branded drug product in
dosage, safety, effectiveness, strength, stability, products use the same active
ingredients as branded drug products and work the same way, So they have the
same risks and benefits as the brand-name medicines. There will always be a
slight level of natural variability for one batch of branded drug products
compared with the next batch of the branded drug product. This variability
occurs during manufacturing, for both branded and generic medicines. When a
generic or branded drug product is mass-produced, very small variations in
purity, size, strength, and other parameters are permitted.

39. 4. Side Effects (Safety Issues) of Generic Drug Products
Once the regulatory agency approves generics, it continues to examine the
generic drug product's safety. The regulator takes several actions to ensure
safety and quality before and after a generic drug product is marketed. The
regulatory agency's staff continually monitors generic drug products to make
certain that the proposed drug product at all levels of the supply chain, from
API to product being sold to consumers, is safe, effective, and high quality.
They also monitor and investigate reports of negative patient side effects or
other reactions.

40. 5. Indian Scenario of Generic Drug Products
The term 'generic' in India denotes the drug products which are marketed under
a generic name. There is another term called 'Branded Generics' that indicates
drug products that are off-patent and sold under a brand name. As India is one
of the highest per r out-of-pocket expenditures' countries, generics help to save
a lot of money that is used for making available other health care facilities. In
2008, the Government of India, through the department of Pharmaceuticals,
started a new initiative "Jan Aushadhi" (Medicine the People).

41. GENERIC DRUG PRODUCT DEVELOPMENT
Drug product development is a creative and multidisciplinary process that turns
a technological innovation and a market opportunity in products with economic
profitability for the company. Generic drug products have played an increasingly
important role in the health care system worldwide, especially in the
developing world, as they provide for an effective and more affordable
alternative for healthcare professionals. Generic drug products are proven
therapeutically equivalent to the corresponding innovator's product, and hence
can be substituted in clinical practice. The objective of generic drug product
development is to develop a stable and bioequivalent generic drug product
with desirable properties. The process of development includes three
sequential stages essential for successful generic drug development.

42. Based on the extensive literature or reviewed, development of the generic
product development process includes the following phases:
1. Drug candidate selection: In this phase, the organization set up a dedicated e
t, team to select multiple solutions for a problem identified by a market survey.
This phases covers the broad selection of potential drug candidates. Rigorous
sessions as brainstorming are conducted to reach to narrow down the list. A
team decides which drug candidates should be selected to proceed into the
preliminary assessment phase.
2. Candidate drug screening: In this phase drug candidates selected in the earlier
phase . carefully screened to roughly assess the potential drug candidates. The
simple strategy followed is to accept the best and eliminate the poor. Thus,
development proceeds with only one or two candidates for the next phase.
This is only desk research or an assessment on paper, which usually covers the
marketing potential, the production possibilities

43. 3. Concept development: It is an exercise in which the screened candidate drug
is translated into the product concept. The product concept is a detailed version
of the product idea. The needs of the target market are identified, alternative
product concepts are generated and evaluated, and a single development is
selected for further development.
4. System-level design: This phase includes the definition of the product
composition and the division of the product into subsystems and components.
The final formulation scheme for the production system is usually defined
during this phase. The output of this phase is usually a product layout with
functional specifications of each of the products components, and a preliminary
process flow diagram for the final manufacturing.

44. 5. Detail design: This phase includes the complete specification of the materials
and limits of all the components in the product and the identification of all the
probable suppliers. A process plan is established within the production system.
The output of this phase is the control documentation for the product.
6. Concept testing: This phase is the laboratory development of a generic
product. This phase starts with experimental and accelerated stability study
work, the development based on a laboratory scale, including the (pilot) bio-
equivalent-study and development of the primary packaging. The scale-up from
the laboratory to the semi-industrial scale is done.

45. 7. Business analysis: It is significant phase for every organization. Landmarks
and milestones of the product development process and time required for
the completion should are fixed. Also, in this phase, the impacts of delays
and time of product arrival in the market are analyzed carefully.
8. Development of a prototype: This phase includes the development of a
prototype, testing of a prototype, modifications in the prototype, and pilot
production. This phase is also called production ramp-up. Ramp up describes
an increase in firm production ahead of anticipated increases in product
demand.

46. 9. Development of technology: This phase includes the transfer to the industry
measure and the preparation of registration documentation. It includes clinical
studies, toxicological studies, bio-equivalent studies, and completed stability
studies. This phase finishes with the production of three registration batches.
The more departments involved in this phase, the shorter is the new product
development process. The more FTE's involved in this phase, the longer is this
phase of the new product development process.
10. Registration: Registration is a phase of filing of registration dossiers at
regulatory authorities, Fig. 1.3. It finishes when the product is registered and
the registration documentation and marketing authorization is obtained.