8.

Unit Wise Notes:

Unit I
Pharmaceutical Regulatory affairs

Drug Regulatory Affairs refers to all aspects within the pharmaceutical development process and how
they are subject to various degrees of regulation. The pharmaceutical law frame, guidelines covering
Quality, Safety and Efficacy as well as Health Authorities' attitudes and requirements etc. have a great
influence on the drug development process and the success of it. Regulatory affairs professionals deal
with these aspects.

Regulatory affairs is a profession developed from the desire of governments to protect public
health by controlling the safety and efficacy of products in areas including pharmaceuticals,
veterinary medicines, medical devices, pesticides, agrochemicals, cosmetics and
complementary medicines, and by the companies responsible for the discovery, testing,
manufacture and marketing of these products wanting to ensure that they supply products that
are safe and make a worthwhile contribution to public health and welfare.
Regulatory Affairs plays a crucial role in the pharmaceutical industry and is involved in all
stages of drug development and also after drug approval and marketing. Throughout the
development stages, pharmaceutical companies have to abide by an array of strict rules and
guidelines in order to ensure safety and efficacy of the drug in humans.
Regulatory Affairs also ensures the maintenance of the marketing licence and leads life cycle
extension activities such as broadening the indication of the drug, change of formulation,
changes in the dosage etc.
Most companies, whether they are major multinational pharmaceutical corporations or small,
innovative biotechnology companies, have specialist departments of Regulatory Affairs
professionals.
Regulatory professionals are responsible for:

1. Keeping track of the ever-changing legislation in all the regions in which a company wishes to
distribute its products.

2. Advising on legal and scientific restraints and requirements.

3. Collecting, collating and evaluating scientific data.

11
 4. Presenting registration documents to regulatory agencies and carrying out any subsequent
negotiations necessary to obtain or maintain marketing authorization for the products
concerned.

5. Giving strategic and technical advice at the highest level in their companies, making an
important contribution both commercially and scientifically to the success of a development
programme and the company as a whole.

6. Helping the company avoid problems caused by badly kept records, inappropriate scientific
thinking or poor presentation of data.

Additionally, the regulatory affairs department will often take part in the development of product
marketing concepts and is commonly required to approve packaging and advertising before it is used
commercially.

Evolution of regulatory affairs

During 1950s, multiple tragedies i.e. sulfanilamide elixir, vaccine tragedy and thalidomide tragedy
have resulted in substantial increase of legislations for drug products quality, safety and efficacy. This
has also resulted into stricter norms for Marketing Authorization (MA) and Good Manufacturing
Practices (GMPs). Let us see what happened in USA, Europe and India.

Sulfanilamide Elixir Tragedy

taste, and fragrance it was flavored with raspberry extract, saccharin, and caramel, among other
ingredients and by September 1937, Massengill had distributed 240 gallons of the liquid, called Elixir
Sulfanilamide, across the country. But commercial success soon soured, as the first deaths were
reported in October: six patients in Tulsa, Oklahoma, died of renal failure following treatment with the
drug. FDA

Diethylene glycol, as the cause of the deaths. But under the regulation
really done anything wrong: analyses of the concoction taken by the Tulsa patients revealed the
ingredients to be exactly what the company had said they were. (The company had only broken the law

12
by calling the medicine an
disaster provoked a public outcry that led to the passage of the 1938 Food, Drug, and Cosmetics Act,
which gave the FDA power to monitor the safety of new drugs.

Thalidomide tragedy

Thalidomide was developed in the 1950s by the West German pharmaceutical company Chemie

drug, but instead it made users sleepy and relaxed. It seemed a perfect example of newly fashionable
tranquilizers. During patenting and testing, scientists realised it was practically impossible to achieve
an LD50 level, or deadly overdose, of the drug. Animal tests did not include tests looking at the effects
of the drug during pregnancy. The apparently harmless thalidomide was licensed in July 1956 for
prescription-free over-the-counter sale in Germany and most European countries. The drug also
reduced morning sickness, so it became popular with pregnant women. By 1960 doctors were
concerned about possible side effects. Some patients had nerve damage in their limbs after long-term
use. Grünenthal did not provide convincing clinical evidence to refute concerns. In the United States,
the Food and Drug Administration (FDA
drug for use.

The thalidomide disaster is one of the darkest episodes in pharmaceutical research history. The drug
was marketed as a mild sleeping pill safe even for pregnant women. However, it caused thousands of
babies worldwide to be born with malformed limbs. The damage was revealed in 1962. Before then,
every new drug was seen as beneficial. Now there was suspicion and rigorous testing.

13
Vaccine tragedy

In USA, the root for vaccine industry development was the vaccine tragedy. In April 1955 more than
200 000 children in five Western and mid-Western USA states received a polio vaccine in which the
process of inactivating the live virus proved to be defective. Within days there were reports of paralysis
and within a month the first mass vaccination programme against polio had to be abandoned.
Subsequent investigations revealed that the vaccine, manufactured by the California-based family firm
of Cutter Laboratories, had caused 40 000 cases of polio, leaving 200 children with varying degrees of
paralysis and killing.

In Europe, due to thalidomide tragedy, 65/65/EEC came into effect mandating marketing authorization.
Pharmaceutical legislations pertaining to drug development as well as marketing authorization
procedure become quite clear and transparent. EMEA committee was developed for centralized
application assessment.

In India, the drug industry has grown from API manufacturing through reverse engineering to pure
research and development. Regulatory Authority of India issued guideline for Fixed Dose
Combination, Implementation of Common Technical Dossier (CTD), Clinical Trial Registry of India
(CTRI) as well as Pharmacovigilance cell.

Terminology used in regulatory affairs

eased and consider that the

product is of acceptable or even high quality. If his or her expectations are not fulfilled, the customer
will consider that the product is of low quality. This means that the quality of a product may be defined

Quality
to satisfy stated or implied needs." For pharmaceutical products, parameters such as physical and
chemical characteristics, medicinal effect, toxicity, taste and shelf life may be important quality
parameters.

Quality assurance is a wide-ranging concept covering all matters that individually or collectively
influence the quality of a product. It is the totality of the arrangements made with the object of ensuring
that pharmaceutical products are of the quality required for their intended use.

14
Quality control covers all measures taken, including the setting of specifications, sampling, testing and
analytical clearance, to ensure that starting materials, intermediates, packaging materials and finished
pharmaceutical products conform with established specifications for identity, strength, purity and other
characteristics.

Standard operating procedure (SOP) refers to an authorized, written procedure giving instructions
for performing operations not necessarily specific to a given product but of a more general nature (e.g.
equipment operation, maintenance and cleaning, validation, cleaning of premises and environmental
control, sampling and inspection.

Expiry date refers to the date given on the individual container (usually on the label) of a product up to
and including which the product is expected to remain within specifications, if stored correctly. It is
established for each batch by adding the shelf-life to the date of manufacture.

Shelf-life refers to the period of time during which a finished pharmaceutical product, if stored
correctly, is expected to comply with the specification as determined by stability studies on a number
of batches of the product. The shelf-life is used to establish the expiry date of each batch.

Auditing is an independent, objective assurance and consulting activity designed to add value and
improve an organization's operations. It helps an organization accomplish its objectives by bringing a
systematic, disciplined approach to evaluate and improve the effectiveness of risk management,
control, and governance processes.

Validation refers to a documented programme that provides a high degree of assurance that a specific
process, method or system will consistently produce a result meeting pre-determined acceptance
criteria.

Good Manufacturing Practice (GMP) is a system for ensuring that products are consistently
produced and controlled according to quality standards. It is designed to minimize the risks involved in
any pharmaceutical production that cannot be eliminated through testing the final product. GMP covers
all aspects of production from the starting materials, premises, and equipment to the training and
personal hygiene of staff. Detailed, written procedures are essential for each process that could affect
the quality of the finished product. There must be systems to provide documented proof that correct
procedures are consistently followed at each step in the manufacturing process - every time a product is
made.

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cGMP refers to the Current Good Manufacturing Practice regulations enforced by the US Food
and Drug Administration (FDA). CGMPs provide for systems that assure proper design, monitoring,
and control of manufacturing processes and facilities. Adherence to the CGMP regulations assures the
identity, strength, quality, and purity of drug products by requiring that manufacturers of medications
adequately control manufacturing operations. This includes establishing strong quality management
systems, obtaining appropriate quality raw materials, establishing robust operating procedures,
detecting and investigating product quality deviations, and maintaining reliable testing laboratories.
This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to
prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug
products meet their quality standards.

GLP (Good Laboratory Practice) refers to a quality system concerned with the organizational
process and the conditions under which non-clinical health and environmental safety studies are
planned, performed, monitored, recorded, archived and reported.

Good Automated Laboratory Practices (GALP) is a standardized set of best practices that are used
to ensure data integrity for laboratory data that is gathered, processed, and archived by a laboratory
information management system (LIMS). The GALP was developed to establish guidelines for
automated data management in laboratories that supply data to the United States Environmental
Protection Agency (EPA). The need for such guidelines has increased as a result of the ongoing shift
from manual to automated procedures. Most data that is submitted to the EPA has been processed in
some way by an LIMS.

Good distribution practice (GDP) deals with the guidelines for the proper distribution of medicinal
products for human use. GDP is a quality warranty system, which includes requirements for purchase,
receiving, storage and export of drugs intended for human consumption.

Good Storage Practices are that part of quality assurance that ensures that the quality of a
pharmaceutical product is maintained through adequate control throughout the storage. Good storage
practice (GSP) is applicable in all circumstances where pharmaceutical products are stored throughout
the distribution process.

The quality of pharmaceutical products can be affected by a lack of adequate control over numerous
activities which occur during the distribution process. Good Trade and Distribution Practices are
that part of quality assurance that ensures that the quality of pharmaceutical products is maintained
16
through adequate control throughout the numerous activities which occur during the trade and the
distribution process.

Good regulatory practices (GRP) may be described as a set of practices that are to be applied to the
development, implementation and maintenance of controls including laws, regulations and guidelines
in order to achieve a public policy objective. GRP can be applied to the preparation and management
of regulations for the control of health products.

Good Documentation Practices are the guidelines that one follows in recording raw data entries in a
legible, traceable and reproducible manner. Good documentation constitutes an essential part of the
quality assurance system and is key to operating in compliance with GMP requirements.

A copyright protects original works of authorship including literary, dramatic, musical, and artistic
works, such as poetry, novels, movies, songs, computer software, and architecture. Copyrighting
provides a person with legal evidence and public notice of ownership. The duration of copyright
protection depends on several factors. For works created by an individual, protection lasts for the life
of the author, plus 70 years. For works created anonymously, pseudonymously, and for hire, protection
lasts 95 years from the date of publication or 120 years from the date of creation, whichever is shorter.

A trademark is a word, phrase, symbol, and/or design that identifies and distinguishes the source of
the goods of one party from those of others. A service mark is a word, phrase, symbol, and/or design
that identifies and distinguishes the source of a service rather than goods. Some examples include:
brand names, slogans, and logos. The term "trademark" is often used in a general sense to refer to both
trademarks and service marks. Registering a trademark enhances the rights of a person by providing
legal evidence and public notice of ownership. It is proof enough of a nationwide exclusive right to the
mark and allows the holder to sue an infringer if the case calls for it.

A patent is a limited duration property right relating to an invention, granted by the Patent and
Trademark Office in exchange for public disclosure of the invention. When a patent is filed, the owner
gets an exclusive right to prevent others from making, using, selling, or importing the protected
invention. Patentable materials include machines, manufactured articles, industrial processes, and
chemical compositions. The duration of patent protection depends on the type of patent granted:

Design Patents - 15 years from issuance for applications filed on or after May 13, 2015 (14 years from
issuance if filed before May 13, 2015)

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Utility patents and plant patents - 20 years from the date on which the application for the patent was
filed in the United States or, in special cases, from the date an earlier related application was filed.

Sponsor: Sponsor means a person who takes responsibility for and initiates a clinical investigation.
The sponsor may be an individual or pharmaceutical company, governmental agency, academic
institution, private organization, or other organization (21 CFR 312.3 (b)).

Drug product: Drug product means a finished dosage form, for example, tablet, capsule, or solution,
that contains a drug substance, generally, but not necessarily, in association with one or more other
ingredients (21 CFR 314.3 (b)).

Drug Substance: Drug substance means an active ingredient that is intended to furnish
pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or
prevention of disease or to affect the structure or any function of the human body, but does not include
intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)).

Code of Federal Regulations (CFR)

The final regulations published in the Federal Register (daily published record of proposed rules, final
rules, meeting notices, etc.) are collected in the CFR. The CFR is divided into 50 titles which represent
broad areas subject to Federal regulations. The FDA's portion of the CFR interprets the Federal Food,
Drug and Cosmetic Act and related statutes. Section 21 of the CFR contains all regulations pertaining
to food and drugs. The regulations document all actions of all drug sponsors that are required under
Federal law.

The following regulations directly apply to the ANDA process:

21CFR Part 314: Applications for FDA Approval to Market a New Drug

21CFR Part 320: Bioavailability and Bioequivalence Requirements

The following regulations apply to the IND application process:

21CFR Part 201 Drug Labeling

21CFR Part 312 Investigational New Drug Application

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 21CFR Part 314 IND and NDA Applications for FDA Approval to Market a New Drug
(New Drug Approval)

21CFR Part 316 Orphan Drugs

21CFR Part 50 Protection of Human Subjects

21CFR Part 54 Financial Disclosure by Clinical Investigators

21CFR Part 56 Institutional Review Boards

21CFR Part 58 Good Lab Practice for Nonclinical Laboratory [Animal] Studies

The following regulations apply to the NDA application process:

21CFR Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic
Drug.

Documentation in Pharmaceutical industry

Importance of Documentation

I. Documentation helps to build up a detailed picture of what a manufacturing function has done
in the past and what it is doing now and, thus, it provides a basis for planning what it is going to
do in the future. Regulatory inspectors, during their inspections of manufacturing sites, often

enhances the visibility of the quality assurance system.

II. Documentation is the key to GMP compliance and ensures traceability of all development,
manufacturing, and testing activities. Documentation provides the route for auditors to assess
the overall quality of operations within a company and the final product. Good documentation
constitutes an essential part of the quality assurance system. Clearly written procedures prevent
errors resulting from spoken communication, and clear documentation permits tracing of
activities performed.
III. Good documentation defines the specifications for all materials and the method of manufacture
and control, to ensure that all personnel concerned with manufacture have the information

19
 necessary to decide whether or not to release a batch of a drug for sale, and to provide an audit
trail that will permit investigation of the history of any suspected defective batch. Documents
must be designed, prepared, reviewed, and distributed with care. Documents must be approved,
signed, and dated by the appropriate competent and authorized persons.
IV. All production, control, and distribution records should be retained for at least 1 year after the
expiry date of the batch. For APIs with retest dates, records should be retained for at least 3
years after the batch is completely distributed. Documents must be regularly reviewed and kept
up-to-date. When a document has been revised, systems must be operated to prevent inadvertent
use of superseded documents (e.g., only current documentation should be available for use).
V. Documents must not be handwritten; however, where documents require the entry of data, these
entries may be made in clear legible handwriting using a suitable indelible medium (i.e., not a
pencil). Sufficient space must be provided for such entries. Any correction made to a document
or record must be signed or initialled and dated; the correction must permit the reading of the
original information. Where appropriate, the reason for the correction must be recorded.
VI. Records of major equipment use, cleaning, sanitization and/or sterilization, and maintenance
should show the date, time (if appropriate), product, and batch number of each batch processed
in the equipment and the name and signature of the person who has performed the cleaning and
maintenance. The persons performing and double-checking the cleaning and maintenance
should date and sign or initial the log, indicating that the work was performed. Entries in the log
should be in chronological order.
VII. Record must be kept at the time each action is taken and in such a way that all activities
concerning the conduct of preclinical studies, clinical trials, and the manufacture and control of
products are traceable. Storage of critical records must at secure place, with access limited to
authorized persons. The storage location must ensure adequate protection from loss, destruction,
or falsification, and from damage due to fire, water, etc. Records which are critical to regulatory
compliance or to support essential business activities must be duplicated on paper, microfilm, or
electronically, and stored in a separate, secure location in a separate building from the originals.

Required GMP documentation

A. Site master file: A document describing the GMP related activities of the manufacturer. It
should contain the following:

a) Instructions (directions, or requirements) type:

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 Specifications: Describe in detail the requirements with which the products or materials used or
obtained during manufacture have to conform. They serve as a basis for quality evaluation.

Manufacturing Formulae, Processing, Packaging and Testing Instructions: Provide detail

all the starting materials, equipment and computerised systems (if any) to be used and specify
all processing, packaging, sampling and testing instructions. In process controls and process
analytical technologies to be employed should be specified where relevant, together with
acceptance criteria.

Standard Operating Procedures: Give directions for performing certain operations.

Protocols: Give instructions for performing and recording certain discreet operations.

Technical Agreements: Are agreed between contract givers and acceptors for outsourced
activities.

b) Record/Report type:

Records: Provide evidence of various actions taken to demonstrate compliance with

instructions, e.g. activities, events, investigations, and in the case of manufactured batches a
history of each batch of product, including its distribution.

Certificates of Analysis: Provide a summary of testing results on samples of products or

materials together with the evaluation for compliance to a stated specification.

Reports: Document the conduct of particular exercises, projects or investigations, together with
results, conclusions and recommendations.

Good Documentation Practices

Handwritten entries should be made in clear, legible, indelible way.

Records should be made or completed at the time each action is taken and in such a way that all
significant activities concerning the manufacture of medicinal products are traceable.

Any alteration made to the entry on a document should be signed and dated; the alteration
should permit the reading of the original information. Where appropriate, the reason for the
alteration should be recorded.
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Master Formula Record

To ensure uniformity from batch to batch, master production instructions for each intermediate or
API/finished product should be prepared, dated, and signed by one person and independently checked,
dated, and signed by a second person in the quality unit(s). Competent persons experienced in
production and quality control should be responsible for the content and distribution within the firm of
instructions and master formulae. These should be duly signed and dated. Outdated master formulae
should be withdrawn but retained for reference. Copies of the master formula should be prepared in a
manner that will eliminate any possibility of transcription error. Processing should be carried out in
accordance with the master formula.

Master production instructions should include:

i. The name of the intermediate/API/formulation being manufactured and an identifying

document reference code, if applicable.

ii. A complete list of raw materials and intermediates.

iii. An accurate statement of the quantity or ratio of each raw material or intermediate to be used,
including the unit of measure. Where the quantity is not fixed, the calculation for each batch
size or rate of production should be included. Variations to quantities should be included
wherever justified.

iv. The production location and major production equipment to be used; detailed production
instructions, including the: Sequences to be followed: Ranges of process parameters to be used.

v. The methods or reference to the methods, to be used for preparing the critical equipment.

vi. Sampling instructions and in-process controls, with their acceptance criteria, where appropriate.

vii. Time limits for completion of individual processing steps and/or the total process, where ever
appropriate.

viii. Expected yield ranges at appropriate phases of processing or time. Special notations and
precautions to be followed.

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 ix. Instructions for storage of the intermediate or API/semi-finished formulations to assure its
suitability for use; instructions should cover the labelling.

Batch production records (BPR)/batch production and control records (BPCR)/batch

manufacturing record (BMR)

Batch production records should be prepared for each intermediate and API/formulation and should
include complete information relating to the production and control of each batch. The batch
production record should be checked before issuance to assure that it is the correct version and a legible
accurate reproduction of the appropriate master production instruction. If the batch production record
is produced from a separate part of the master document, that document should include a reference to
the current master production instruction being used. Documentation of completion of each significant
step in the batch production records (batch production and control records) should include:

i. Dates and, when appropriate, times; Identity of major equipment used; Specific identification of
each batch, including weights, measures, and batch numbers of raw materials, intermediates, or
any reprocessed materials used during manufacturing; Actual results recorded for critical
process parameters

ii. Any sampling performed; Signatures of the persons performing and directly supervising or
checking each critical step in the operation; In-process and laboratory test results.

iii. Actual yield at appropriate phases or times; Description of packaging and label.

iv. Representative label (commercial supply); Any deviation noted, its evaluation, and
investigation conducted (if appropriate) or reference to that investigation (if stored separately)

v. Results of release testing; all analytical records relating to the batch, or a reference that will
permit their retrieval.

vi. A decision for the release or rejection of the batch, with the date and signature of the person
responsible for the decision.

vii. The production record review.

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Drug Master File

A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be
used to provide confidential detailed information about facilities, processes, or articles used in the
manufacturing, processing, packaging, and storing of one or more human drugs. The submission of a
DMF is not required by law or FDA regulation. A DMF is submitted solely at the discretion of the
holder. The information contained in the DMF may be used to support an Investigational New Drug
Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA),
another DMF, an Export Application, or amendments and supplements to any of these. A DMF is NOT
a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved.
Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA,
ANDA, or an Export Application.

Drug Master Files are provided for in 21 CFR 314.420. This guideline is intended to provide DMF
holders with procedures acceptable to the agency for preparing and submitting a DMF. The guideline
discusses types of DMF's, the information needed in each type, the format of submissions to a DMF,
the administrative procedures governing review of DMF's, and the obligations of the DMF holder.

There are five types of drug master files:

Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel. Type I DMFs are no
longer accepted as per a Final Rule published January 12, 2000. A Type I DMF is recommended for a
person outside of the United States to assist FDA in conducting on site inspections of their
manufacturing facilities.

Type II: Drug Substance (DS), Drug Substance Intermediate, and Material Used in Their Preparation,
or Drug Product (DP). In case of drug substance (DS), summarize all significant steps in the
manufacturing and controls of the drug intermediate or substance. Whereas, in case of drug product
(DP), manufacturing procedures and controls for finished dosage forms should ordinarily be submitted
in an IND, NDA, ANDA, or Export Application.

Type III: Packaging Material. Each packaging material should be identified by the intended use,
components, composition, and controls for its release. Toxicological data on these materials would be
included under this type of DMF, if not otherwise available by cross reference to another document.

24
Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation. Each additive
should be identified and characterized by its method of manufacture, release specifications, and testing
methods. Toxicological data on these materials would be included under this type of DMF. Usually, the
official compendia and FDA regulations (21 CFR) may be used as sources for release tests,
specifications, and safety.

Type V: FDA Accepted Reference Information. If any holder wishes to submit information and
supporting data in a DMF that is not covered by Types I through IV. DMF holders wishing to submit a
Type V DMF must obtain clearance from the FDA. FDA discourages the use of Type V DMF's for
miscellaneous information, duplicate information, or information that should be included in one of the
other types of DMF's.

Holders of Type II, III, and IV DMFs do not need to place information regarding facilities, personnel or
general operating procedures in these DMFs. Only the addresses of the DMF holder and
manufacturing site and contact personnel should be submitted. Type II, Type III, and Type IV DMF's
should contain a commitment by the firm that its facilities will be operated in compliance with
applicable environmental laws. If a completed environmental assessment is needed, see 21 CFR Part
25.

Submissions to Drug Master Files

Each DMF submission should contain a transmittal letter, administrative information about the
submission, and the specific information to be included in the DMF as described in this section.

The DMF must be in the English language. Whenever a submission contains information in another
language, an accurate certified English translation must also be included. Each page of each copy of
the DMF should be dated and consecutively numbered. An updated table of contents should be
included with each submission. DMFs should be submitted following the Common Technical
Document (CTD) format recommended in the "Guidance for Industry M4Q: The CTD - Quality"
(CTD-Q
ICH-CTD Format

Drug Master File Review: A DMF IS NEVER APPROVED OR DISAPPROVED. After receipt, the
original DMF undergoes an administrative review to determine whether it is administratively
complete. This administrative review may take 2-3 weeks. If the DMF is acceptable from an

25
administrative point of view, an Acknowledgement Letter will be issued, notifying the holder of the
DMF number. At this point the DMF is "ACTIVE." If it is not acceptable from an administrative
point of view, the holder will be notified of what deficiencies need to be corrected in order to make the
DMF "Active".

FDA does not acknowledge, whether via e-mail or letter, any submission after the original DMF. All
submissions to an existing DMF undergo an administrative review to determine whether they are
administratively complete. If a submission to an existing DMF is not acceptable from an administrative
point of view, the holder will be notified of what deficiencies need to be corrected in order to make the
submission acceptable.

Distribution Records

Distribution is the division and movement of pharmaceutical products from the premises of the
manufacturer of such products, or another central point, to the end user thereof, or to an intermediate
point by means of various transport methods, via various storage and/or health establishments.
Pharmaceutical products should only be distributed to persons or entities that are entitled to acquire
such products in terms of applicable national, regional and international legislation. Written proof of
such authority must be obtained prior to the dispatch of products to such person or entities. The
supplier of pharmaceutical products should, prior to the dispatch of such products, ensure that the
person or entity, e.g. the contract acceptor for transportation of the pharmaceutical products, is aware of
and follows the appropriate storage and transport conditions.

26
Prior to distribution or dispatch of given batch of a drug, it shall be ensure that the batch has been duly
tested, approved and released by the quality control personnel. Pre-dispatch inspection shall be
performed on each consignment on a random basis to ensure that only the correct goods are dispatched.
Detailed instructions for warehousing and stocking of Large Volume Parenterals, if stocked, shall be in
existence and shall be complied with after the batch is released for distribution.

Periodic audits of warehousing practices followed at distribution centers shall be carried out and
records thereof shall be maintained. Standard Operating Procedures shall be developed for warehousing
of products. Records for distribution shall be maintained in a manner such that finished batch of a drug
can be traced to the retain level to facilitate prompt and complete recall of the batch, if and when
necessary.

Pharmaceutical products should not be supplied or received after their expiry date, or so close to the
expiry date that this date is likely to occur before the products are used by the consumer.

Written instructions and records should be available, which document all activities relating to the
distribution of pharmaceutical products, including all applicable receipts and issues. The name of the
applicable entity should appear on all relevant documents. The title, nature and purpose of each
document should be clearly stated. The contents of documents should be clear and unambiguous.
Documents should be laid out in an orderly fashion and be easy to check. Documents, in particular
instructions and procedures relating to any activity that could have an impact on the quality of
pharmaceutical products, should be designed, completed, reviewed and distributed with care.

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 Unit-II
Regulatory Requirement for Product Approval

Registration of drugs in United States

Foreign drug establishments whose drugs are imported or offered for import into the United States are
required to register with FDA and submit listing information for their drugs intended for commercial
distribution in the United States. If the foreign manufacturer has not been previously registered, they
are required to register with the FDA within 5 days after submitting a drug application, biological
license application, or medicated feed mill license application. Registration is required within 5 days of
introducing product into commercial distribution. Annual renewal of registration must occur between
October 1 and December 31 of each year.
For the submission of Drug Registration and Listing data, FDA has adopted the use of Extensible
Markup Language (XML) files in the Structured Product Labeling (SPL) format. To transmit the SPL
Electronic Submission Gateway (ESG). There are
three steps, or submissions, that are needed in order to register an establishment and list a drug with
FDA:
a) Establishment Registration
b) Labeler Code Form
c) Product Listing
Each of these steps requires an initial submission, followed by periodic updates/renewals to maintain
an accurate and current status.
Establishment Registration
With certain exemptions, any establishment engaged in the manufacture, repacking, relabeling, or
salvaging of a drug product for commercial distribution is required to register with FDA. Some
exemptions include (but not limited to):
I. Pharmacies that:
i. Operate in conformance with all applicable local laws regulating the practice of
pharmacy and medicine;
ii. Regularly engage in dispensing prescription drugs upon a valid prescription; and
iii. Do not manufacture, repack, relabel, or salvage drugs other than in the regular course of
their business of dispensing or selling drugs at retail.
II. Hospitals, clinics, other health care entities, and public health agencies that:

28
 i. Operate establishments in conformance with all applicable local laws regulating the
practice of pharmacy and medicine;
ii. Regularly engage in dispensing prescription drugs upon a valid order or prescription;
iii. Do not manufacture, repack, relabel, or salvage drugs other than in the regular course of
their practice of pharmacy, including dispensing;
III. Practitioners who are licensed by law to prescribe or administer drugs and who manufacture,
repack, relabel, or salvage drugs solely for use in their professional practice;
IV. Manufacturers, repackers, relabelers, or salvagers who manufacture, repack, relabel, or salvage
drugs solely for use in research, teaching, or chemical analysis and not for sale;
V. Manufacturers, repackers, and relabelers of harmless inactive ingredients such as excipients,
colorings, flavorings, emulsifiers, lubricants, preservatives, or solvents that become components
of drugs;
VI. Carriers, in their receipt, carriage, holding, or delivery of drugs in the usual course of business
as carriers; and
VII. Storage facilities which do not perform any manufacturing function.
Registration Process
To register with FDA, create and submit an Establishment Registration SPL document. Be sure to save
a copy of your submission. Remember to include:
The name and Dun and Bradstreet Verification (DUNS) number of the establishment (not one
linked to the corporate HQ); (FDA has begun an initiative to verify facility information that has
be )
Contact information of someone responsible for receiving FDA communications related to that
establishment;
All applicable business operations that establishment performs; and
For foreign establishments, the name and DUNS of a U.S. agent and all importers.
To update or renew a registration:
If there are no changes to existing establishment or contact information, create a No Changes
Notification SPL document. Fill in the SetID (Globally Unique Identifier for the document that
remains constant through all versions/revisions of the document.) Enter the appropriate
effective date and version number (generally, one number higher than the previous submission)
and submit.
If there are changes/updates to existing establishment data:
Create a copy/new version of the most recent submission;
29
 Do not change the SetID. Retain the original SetID from the previous version;
Generate a new DocumentID / RootID (Globally Unique Identifier for each version of an SPL

Enter an appropriate effective date and version number (generally, one number higher than the
previous submission);
Modify all establishment and contact information as appropriate; and Submit.
Labeler Codes
Labeler codes are only used for generating National Drug Code (NDC) numbers for drugs. Generally,
if you do not have to list any drugs with FDA, you do not need to apply for a labeler code. Under most
circumstances, an assigned labeler code that does not have any NDCs listed with FDA within two years
will be deactivated. Since the labeler code identifies a company marketing a product, a company is not
required to obtain a different labeler code for each manufacturing establishment under the same
ownership.
Listing
All registered establishments must list all of the products they produce for commercial distribution
under their own labeler code. This includes API manufacturers, other bulk manufacturers, contract
manufacturers, repackers, and relabelers.
A single product listing SPL may include multiple NDCs (products and packages) provided that they
all use the same content of labeling/package insert. For example, a single product listing SPL may

counts of 50, 100, or 200 tablets. Note: as the outer labeling varies for each product and package in this
case, multiple carton images may be required to represent all the variations.
Initial product listings should be submitted within three days after initial registration of the
establishment. FDA recommends that updates to listing data should be made immediately. However,
they are required to be made no later than June or December following a change in the information. For

certification once a year during the October 1 to December 31 renewal period.

To list a product:
Select the appropriate SPL document type for the product (Human Rx Drug, Human OTC, Bulk
Ingredient, etc.);
Fill out all required listing data elements;
For labeling, create a section within the SPL file for each section of content (e.g. Highlights,
Warnings, How Supplied, etc.) and enter the text for each; and
30
 a. The JPG file(s) of the outer packaging/front label belongs in the section
entitled Package Label. Principal Display Panel
Submit.
Types of Drug Applications
A. New Drug Application
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 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 drugs 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.
Guidance Documents for NDAs
Guidance documents represent the FDA's current thinking on a particular subject. These documents are
prepared for FDA review staff and applicants/sponsors to provide guidelines to the processing, content,
and evaluation/approval of applications and also to the design, production, manufacturing, and testing
of regulated products.
a. Bioavailability (BA) and Bioequivalence (BE) Studies Submitted in NDAs or INDs: This
guidance contains advice on how to meet the BA and BE requirements set forth in 21 CFR part
320 as they apply to dosage forms intended for oral administration. The guidance may also be
applicable to non-orally administered drug products when reliance on systemic exposure
measures is suitable to document BA and BE (e.g., transdermal delivery systems and certain
rectal and nasal drug products).

method available to demonstrate BA or BE of a product (21 CFR 320.24(a)). As noted in

21CFR 320.24, several in vivo and in vitro methods can be used to measure BA and to establish
BE. These include pharmacokinetic (PK) studies, in vitro tests predictive of human in vivo BA
(in vitro-in vivo correlation), pharmacodynamics (PD) studies, studies with clinical benefit

31
 endpoints, and other in vitro studies. This guidance predominantly focuses on the use of PK
studies to document BA or BE.
b. Changes to an Approved NDA or ANDA: This guidance provides recommendations to
holders of new drug applications (NDAs) and abbreviated new drug applications (ANDAs) who
intend to make post approval changes in accordance with section 506A of the Federal Food,
Drug, and Cosmetic Act (the Act) and § 314.70 (21 CFR 314.70). The guidance covers
recommended reporting categories for post approval changes for drugs other than specified
biotechnology and specified synthetic biological products.
c. A major change is a change that has a substantial potential to have an adverse effect on the
identity, strength, quality, purity, or potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product. A major change requires the submission of a
supplement and approval by FDA prior to distribution of the drug product made using the
change. This type of supplement is called, and should be clearly labeled, a Prior Approval
Supplement (§ 314.70(b)).
d. A moderate change is a change that has a moderate potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product as these factors may relate to
the safety or effectiveness of the drug product. There are two types of moderate change. One
type of moderate change requires the submission of a supplement to FDA at least 30 days
before the distribution of the drug product made using the change. This type of supplement is
called, and should be clearly labeled, a Supplement - Changes Being Effected in 30 Days (§
314.70 (c) (3)).
A minor change is a change that has minimal potential to have an adverse effect on the
identity, strength, quality, purity, or potency of the drug product as these factors may relate to
the safety or effectiveness of the drug product. The applicant must describe minor changes in its
next Annual Report (§ 314.70(d)).
e. Container Closure Systems for Packaging Human Drugs and Biologics: This document is
intended to provide guidance on general principles for submitting information on packaging
materials used for human drugs and biologics. The Federal Food, Drug, and Cosmetic Act (the
Act) mandates the need for adequate information related to packaging materials. Section
501(a)(3) of the Act states that a drug is deemed to be adulterated "if its container is composed,
in whole or in part, of any poisonous or deleterious substance which may render the contents
injurious to health...." In addition, section 502 of the Act states that a drug is considered
misbranded if there are packaging omissions. Also, section 505 of the Act requires a full
32
 description of the methods used in, and the facilities and controls used for, the packaging of
drugs.
A packaging component means any single part of a container closure system. Typical
components are containers (e.g., ampoules, vials, bottles), container liners (e.g., tube liners),
closures (e.g., screw caps, stoppers), closure liners, stopper overseals, container inner seals,
administration ports (e.g., on large-volume parenterals (LVPs)), overwraps, administration
accessories, and container labels. A primary packaging component means a packaging
component that is or may be in direct contact with the dosage form. A secondary packaging
component means a packaging component that is not and will not be in direct contact with the
dosage form.
A container closure system refers to the sum of packaging components that together contain
and protect the dosage form. This includes primary packaging components and secondary
packaging components, if the latter are intended to provide additional protection to the drug
product. A packaging system is equivalent to a container closure system.
A package or market package refers to the container closure system and labeling, associated
components (e.g., dosing cups, droppers, spoons), and external packaging (e.g., cartons or
shrink wrap). A market package is the article provided to a pharmacist or retail customer upon
purchase and does not include packaging used solely for the purpose of shipping such articles.
f. Format and Content of the Microbiology Section of an Application: Antimicrobial drugs
differ from other classes of drugs in that they are intended to affect microbial, rather than
patient, physiology. For this reason, the technical reports of in vivo and in vitro effects on
microorganisms are critical for establishing effectiveness. This guideline is intended to assist
drug firms in preparing the summary to a new drug application required under 21 CFR
314.50(c). The guideline is issued under 21 CFR 10. 90.
g. Format and Content of the Clinical and Statistical Sections of an Application: This
guideline is intended to assist an applicant in presenting the clinical and statistical data required
as part of an application under 21 CFR 314.50. The guideline describes an acceptable format for
organizing the clinical and statistical sections and presenting the clinical and statistical
information and accompanying statistical documentation of a clinical trial.

33
 B. IND (Investigational New Drug)
It is an application to the FDA to obtain exemption from the status that prohibits an unapproved drug
from being transported via interstate commerce. This is precursor of an NDA. IND requires three major
types of documentation:
Animal toxicology and Pharmacology data

34
 Clinical protocol and investigators qualification
CMC (Chemistry, Manufacturing and Control), where some of the physicochemical information
of the drug is required.
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.
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 must contain information in three broad 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 is any
previous experience with the drug in humans (often foreign use).
35
 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.
Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical
studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also,
information on the qualifications of clinical investigators--professionals (generally physicians)
who oversee the administration of the experimental compound--to assess whether they are
qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent
from the research subjects, to obtain review of the study by an institutional review board (IRB),
and to adhere to the investigational new drug regulations.
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.

36
C. Abbreviated New Drug Application (ANDA)

An abbreviated new drug application (ANDA) contains data which is submitted to FDA for the
review and potential approval of a generic drug product. Once approved, an applicant may
manufacture and market the generic drug product to provide a safe, effective, lower cost alternative
to the brand-name drug it references.
A generic drug product is one that is comparable to an innovator drug product in dosage form,
strength, route of administration, quality, performance characteristics, and intended use. All
approved products, both innovator and generic, are listed in FDA's Approved Drug Products with
Therapeutic Equivalence Evaluations.
Generic drug applications are termed "abbreviated" because they are generally not required to
include preclinical (animal) and clinical (human) data to establish safety and effectiveness. Instead,
generic applicants must scientifically demonstrate that their product is performs in the same manner
as the innovator drug. One way applicants demonstrate that a generic product performs in the same
way as the innovator drug is to measure the time it takes the generic drug to reach the bloodstream

bioavailability, of the generic drug, which can then be compared to that of the innovator drug. To
be approved by FDA, the generic version must deliver the same amount of active ingredients into a
patient's bloodstream in the same amount of time as the innovator drug.
The "Drug Price Competition and Patent Term Restoration Act of 1984," also known as the Hatch-
Waxman Amendments, established bioequivalence as the basis for approving generic copies of
drug products. These Amendments permit FDA to approve applications to market generic versions
of brand-name drugs without repeating costly and duplicative clinical trials to establish safety and
efficacy. Under the Hatch-Waxman Amendments, brand-name companies gained patent term
extension to account for the time the patented product is under review by FDA and also gained
certain periods of marketing exclusivity. In addition to the ANDA approval pathway, generic drug
companies gained the ability to challenge patents in court prior to marketing as well as 180-day
generic drug exclusivity.

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38
New drug therapy approval in USA

wide range of patients suffering from many different medical conditions from rare disorders to
common diseases to gain new hope for improved quality of life, and in some cases, improved chances
of surviving life-threatening illnesses.
Rare Diseases
Among many other new approvals to help patients with rare diseases, in 2017 CDER approved the first
new treatment for patients with sickle cell disease in almost 20 years and the first-ever non-blood
product to treat patients with hemophilia A with inhibitors. For the first time, a treatment is available
for adults diagnosed with giant cell arthritis, a rare condition that results in inflammation of blood
vessels. CDER also approved a new treatment for the rare condition known as Batten disease, which
can cause seizures, dementia, and a variety of other debilitating symptoms.
Infectious Diseases
CDER approved a new antibiotic to treat certain types of serious skin infections, and another to treat
complicated urinary tract infections, including kidney infections. We also approved two new treatments
for certain patients with chronic hepatitis C; a new drug to help prevent cytomegalovirus infection in
patients who have received a bone marrow transplant; and, the first therapy in the United States to treat
Chagas disease, a rare parasitic disease which, after years of infection, can cause serious heart illness.
Neurological Disorders
Last year was a particularly productive year for approving new therapies for patients with neurological
disorders. CDER approved new therapies to treat patients with tardive dyskinesia, a frequent side effect
of psychiatric medications, myasthenia gravis, a rare neuromuscular disease, and new treatments for
Duchenne muscular dystrophy, for certain forms of multiple sclerosis, for amyotrophic lateral sclerosis

Cancer Therapies
Year 2017 was also another strong year for making new cancer therapies available to patients in need.
Among others, CDER approved new therapies for certain patients with acute lymphoblastic leukemia;
Merkel cell carcinoma; certain forms of relapsed or refractory acute myeloid leukemia; certain forms of
lymphoma; recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer; and specific forms
of liver, breast, and colorectal cancer. CDER also approved the first cancer treatment based on a
genetic feature of a cancer rather than the location of the body where the tumor originated.

39
Other Advances
Also in 2017, CDER approved a new therapy for decreasing heart risk for patients with diabetes, a new
drug to treat adults with moderate to-severe eczema and three therapies to treat patients with moderate
to-severe plaque psoriasis. Two of these were for adults and one was for adolescents. CDER also
approved the first drug in the United States with a sensor embedded in the pill that records that the
medication was taken. And in response to the devastation inflicted by the 2017 Hurricane Season,
CDER worked with pharmaceutical manufacturers with facilities in affected areas to address potential
drug shortages.

In 2017, CDER approved a wide variety of drug therapies to improve the health of the American
public, including:
Novel drugs, which are often among the more innovative products in the marketplace, and/or
help advance clinical care by providing therapies never before marketed in the United States. In
2017, CDER approved 46 novel drugs, either as new molecular entities (NMEs) under New
Drug Applications (NDAs), or as new therapeutic biologics under Biologics License
Applications (BLAs). Some important examples are given below:

Name of drug product Drug name Indications

Steglatro tablets Ertugliflozin To improve glycemic control in adults with
type 2 diabetes mellitus
Rhopressa ophthalmic solution Netarsudil To treat glaucoma or ocular hypertension

Ozempic Semaglutide To improve glycemic control in adults with

Pre-filled, disposable, single- type 2 diabetes mellitus
patient-use injection pen
Hemlibra injection Emicizumab To prevent or reduce the frequency of
bleeding episodes in adult and pediatric
patients with hemophilia A who have
developed antibodies called Factor VIII
(FVIII) inhibitors.
Fasenra injection Benralizumab For add-on maintenance treatment of patients
with severe asthma aged 12 years and older,
and with an eosinophilic phenotype
Vyzulta ophthalmic solution Latanoprostene To treat intraocular pressure in patients with
open-angle glaucoma or ocular hypertension.

40
Use of Expedited Development and Review Pathways for approval of novel drugs
CDER used several regulatory pathways to expedite the development and approval of novel drugs in
2017. These pathways utilize a range of approaches that can enhance development efficiency and
shorten timelines; these approaches can include more interactions between CDER staff and drug
developers, greater program design flexibility, and shortened timelines for review of applications.
a) Fast Track: Fast Track designated drugs have the potential to address unmet medical needs.
Eighteen of the 46 2017 novel drugs (39%) were designated by CDER as Fast Track. Fast Track
speeds new drug development and review, for instance, by increasing the level of
communication between FDA and drug developers, and by enabling CDER to review portions
of a drug application ahead of the submission of the complete application. Drugs designated
with Fast Track status were: Aliqopa, Bavencio, Baxdela, Bevyxxa, Emflaza, Idhifa, Ingrezza,
Mavyret, Mepsevii, Ocrevus, Prevymis, Rydapt, Solosec, Vabomere, Verzenio, Vosevi,
Xermelo, and Zejula.
b) Breakthrough Therapy: Breakthrough therapies are drugs with preliminary clinical evidence
demonstrating that the drug may result in substantial improvement on at least one clinically
significant endpoint (e.g., study result) over other available therapies for serious or life-
threatening diseases for which there is unmet medical need. CDER designated 17 of the 2017
novel drugs (37%) as breakthrough therapies. A breakthrough therapy designation includes all
the Fast Track program features, as well as more intensive FDA guidance on an efficient drug
development program. Breakthrough therapy designation is designed to help shorten the
development time of a potential new therapy. Drugs designated with Breakthrough therapy
status were: Alunbrig, Bavencio, Besponsa, Brineura, Calquence, Dupixent, Hemlibra, Imfinzi,
Ingrezza, Kisqali, Mavyret, Ocrevus, Prevymis, Rydapt, Verzenio, Vosevi, and Zejula
c) Priority Review A drug receives a Priority Review if CDER determines that the drug could
potentially provide a significant advance in medical care. The drug is reviewed within six
months instead of the standard 10 months. Twenty-eight of the 46 novel drugs approved in 2017
(61%) were designated Priority Review. Note, in some instances, priority review is assigned as

Voucher program, which may mean the drug does not potentially provide a significant advance.
Such drugs are not included in the list below. Drugs designated Priority Review were: Aliqopa,
Alunbrig, Bavencio, Baxdela*, benznidazole, Besponsa, Bevyxxa, Brineura, Calquence,
Dupixent, Emflaza, Giapreza, Hemlibra, Idhifa, Imfinzi, Ingrezza, Kisqali, Mavyret, Mepsevii,
Ocrevus, Prevymis, Rydapt, Solosec*, Vabomere*, Verzenio, Vosevi, Xermelo, and Zejula.
41
 d) Accelerated Approval: The Accelerated Approval program allows FDA more flexibility in
what endpoints can be used to approve a drug that offers a benefit over current treatments for a
serious or life threatening illness. These accelerated approval endpoints may include ones that
show benefits over a shorter duration of treatment (where longer term demonstration of benefit

clinical benefit will be seen. Subsequent confirmatory trials must be conducted to support full
approval. CDER approved six of the 2017 novel drugs (13%) under the Accelerated Approval
program. The application of accelerated approval brings drugs that can provide important
advances to patients sooner than with traditional approvals. Novel drugs approved in 2017 that
received the Accelerated Approval designation were: Aliqopa, Alunbrig, Bavencio,
benznidazole, Calquence, and Imfinzi.
New and expanded uses for already FDA-approved drugs: After CDER approves a new
drug, it is not uncommon for a manufacturer to submit an application with new data that
demonstrate safety and effectiveness of the same product for an additional purpose or for use in
a different population of patients. Applications to modify the use of an already-approved drug
or to expand its use to other patients are in a category of supplemental applications known as

i. Actemra (tocilizumab), originally approved in 2010 to treat patients with rheumatoid arthritis.
It was approved in May 2017 for a new use to treat adults diagnosed with giant cell arteritis, a
form of vasculitis, which is a group of disorders that results in inflammation of blood vessels.
This is the first FDA-approved therapy specifically for this type of vasculitis. In August 2017,
Actemra was also approved to treat patients 2 years of age and older with severe or life-
threatening complications of cytokine release syndrome, a condition related to a reaction caused
by a treatment called chimeric antigen receptor (CAR) T cell therapy.
ii. Victoza (liraglutide), originally approved in 2010 to treat patients with type 2 diabetes. In 2017,
CDER expanded the approved use of the drug to include treatment for reducing risks of heart
attack, stroke and cardiovascular deaths in patients with type 2 diabetes.
Biosimilars: An FDA-approved biosimilar is biological product highly similar to and has no
clinically meaningful differences in terms of safety, purity and potency (safety and
effectiveness) from an already FDA-approved biological product, called the reference product.
Biological products are highly complex, and often used to treat patients with serious and life-
threatening conditions. The law allowing FDA to approve biosimilars was designed to create
competition, increase consumer choice, and support greater access to important therapies.
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 i. Cyltezo (adalimumab-adbm), biosimilar to Humira (adalimumab), approved for the
treatment of patients with rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing
spondylitis, psoriatic arthritis, Crohn
ii. Ogivri (trastuzumab-dkst) biosimilar to Herceptin (trastuzumab), for the treatment of
patients with breast or metastatic stomach cancer (gastric or gastro esophageal junction
adenocarcinoma) whose tumors overexpress the HER2 gene.
Multiple biosimilars for each FDA-approved reference product can make market competition even
stronger. An increase in market competition may lead to significantly reduced costs for both patients
and our healthcare system. The biopharmaceutical industry has shown great interest in developing these
products, and CDER expects many more applications for biosimilars to be submitted. There are
currently nine FDA-approved biosimilars, but there are many more in the development pipeline.
New formulations:
is already FDA-approved. New formulations of already approved drugs can offer significant
advances in therapy. CDER approved three new formulations of already approved opioid pain
medications in 2017-- oxycodone, hydrocodone, and morphine sulfate. These new formulations
have properties that are intended to deter abuse of these highly addictive medications. Although
these products are formulated to make abuse more difficult, they cannot prevent abuse by all
routes, nor are they expected to prevent or reduce addiction. Some examples are given below:
i. Arymo ER (morphine sulfate extended-release tablets), designed with inactive ingredients
that make the tablet more difficult to manipulate for misuse and abuse, and thereby deter
intravenous abuse. Arymo ER is the third morphine sulfate product approved by CDER with
properties designed to deter abuse --- following the 2009 approval of Embeda and the 2015
approval of Morphabond.
ii. Roxybond (oxycodone immediate-release tablets), the first FDA-approved immediate-
release opioid with properties designed to deter abuse by the intravenous and intranasal
(snorting) routes. To date, CDER has approved ten opioid products with properties intended
to deter abuse, but all except Roxybond are extended release/long acting (ER/LA)
preparations.
New dosage forms: New dosage forms for already FDA-approved drugs can improve patient
health by helping to increase patient adherence to therapy, ensure a proper dose is taken, and
improve quality of life for patients who must use the medication on a prolonged basis. Notable
approvals in this category include:

43
 i. Esbriet (pirfenidone) 534 mg. and 801 mg. tablets, new dosage forms of a 267 mg. capsule
originally approved in 2014 as the first new drug in the United States to treat patients with
idiopathic pulmonary fibrosis. A typical dose of the originally approved product is two or
three 267 mg. capsules three times daily. The higher strength tablets enable taking fewer
tablets daily;
ii. Norvir (ritonavir) oral powder, a new dosage form of the tablet and oral solution forms of
Norvir, an HIV protease inhibitor approved in 1996 to be used in combination with other
antiretroviral agents for the treatment of HIV-1 infection. The oral powder formulation can
be mixed in soft foods and does not contain ethanol or propylene glycol and therefore may
be a more palatable and safer alternative for children.

Regulatory Requirements and Drug Approval Process in India

regulate the import, manufacture, distribution and sale of drugs and cosmetics. The Central Drugs
Standard Control Organization (CDSCO) and the office of its leader, the Drugs Controller General
(DCGI) was established. In 1988, the Indian government added Schedule Y to the Drug and Cosmetics
Rules 1945. Schedule Y provides the guidelines and requirements for clinical trials, which was further
revised in 2005 to bring it at par with internationally accepted procedure. When a company in India
wants to manufacture/ import a new drug it has to apply to seek permission from the licensing authority
(DCGI) by filing in Form 44 also submitting the data as given in Schedule Y of Drugs and Cosmetics
Act 1940 and Rules 1945 [4]. In order to prove its efficacy and safety in Indian population it has to
conduct clinical trials in accordance with the guidelines specified in Schedule Y and submit the report
of such clinical trials in specified format.
Rule
122A of the Drug and Cosmetics Act says that the clinical trials may be waived in the case of new
drugs which are approved and being used for several years in other countries. Section 2.4 (a) of
Schedule Y of Drugs and Cosmetics Act 1940 and Rules 1945 says for those drug substances which are
discovered in India all phases of clinical trials are required. Section 2.4(b) of Schedule Y of Drugs and
Cosmetics Act 1940 and Rules 1945 says that for those drug substances which are discovered in
countries other than India; the applicant should submit the data available from other countries and the
licensing authority may require him to repeat all the studies or permit him to proceed from Phase III
clinical trials. Demonstration of safety and efficacy of the drug product for use in humans is essential
before the drug product can be approved for import or manufacturing of new drug by the applicant by
44
Central Drugs Standard Control Organization (CDSCO). The regulations under Drugs and Cosmetics
Act 1940 and its rules 1945, 122A, 122B and 122D describe the information required for approval of
an application to import or manufacture of new drug for marketing [3]. For an investigational new
drug, the sponsor needs to provide detailed information to the DCGI about:
1. Generic name
2. Patent status
3. Brief description of physico-chemical/biological
4. Technical information
a) Stability
b) Specifications
c) Manufacturing process
d) Worldwide regulatory status
e) Animal pharmacology and toxicity studies
5. Published clinical trial reports
6. Proposed protocol and pro forma
7. Trial duration
8. Drug master file
9. Undertaking to Report Serious or Life-threatening Adverse Drug Reactions.
The need for local clinical trials in India depends on the status of drug in other countries. If the drug is
already approved in other countries, generally Phase III trials are required. Phase I trials are not
allowed in India unless the data is available from other countries. Permission is granted by DCGI to
conduct Phase 1 trials in India, if the drug has special relevance to a health problem in India, like
malaria or tuberculosis.
Bioavailability and bioequivalence (BABE) studies should be conducted as per BABE guidelines.
The comprehensive information on the marketing status of the drug in other countries is also required
other than the information on safety and efficacy. The information regarding the prescription, samples
and testing protocols, product monographs, labels must also be submitted. It usually takes 3 months for
clinical trial approval in India. The clinical trials can be registered in the Clinical Trials Registry of
India (CTRI) giving details of the clinical trials and the subjects involved in the trials [6]. The rules to
be followed under The Drugs and Cosmetics Rules 1945 are:
1. Rule 122 - A: Application for permission to import new drug
2. Rule 122- B: Application for approval to manufacture new drug other than the drugs specified under
Schedule C and C (1).
45
3. Rule 122 - D: Permission to import or manufacture fixed dose combination.
4. Rule 122 - DA: Application for permission to conduct clinical trials for New Drug/Investigational
New Drug.
5. Rule 122 - DAB: Compensation in the case of injury or death during the clinical trials.
The changes in the Drugs and Cosmetics Act includes, establishing definitions for Phase I- IV trials
and clear responsibilities for investigators and sponsors. The clinical trials were further divided into
two categories in 2006. In one category (category A) clinical trials can be conducted in other markets
with competent and mature regulatory systems whereas the remaining ones fall in to another category
(category B) Other than A. Clinical trials of category A (approved in the U.S., Britain, Switzerland,
Australia, Canada, Germany, South Africa, Japan and European Union) are eligible for fast tracking in
India, and are likely to be approved within eight weeks. The clinical trials of category B are under more
scrutiny, and approve within 16 to 18 weeks. An application to conduct clinical trials in India should be
submitted along with the data of chemistry, manufacturing, control and animal studies to DCGI. The
date regarding t
also be attached [2,3]. A copy of the application must be submitted to the ethical committee and the
clinical trials are conducted only after approval of DCGI and ethical committee.
Stages of approval
1. Submission of Clinical Trial application for evaluating safety and efficacy.
2. Requirements for permission of new drugs approval.
3. Post approval changes in biological products: quality, safety and efficacy documents.
4. Preparation of the quality information for drug submission for new drug approval.
Most countries have adopted the CTD format. Hence, CDSCO has also decided to adopt CTD format
for technical requirements for registration of pharmaceutical products for human use.

46
47
Drug Approval Process in Europe
The European Medicines Evaluation Agency (EMEA) was established in London, in the year 1995, to
coordinate the European Union (EU) member states for evaluating and supervising the medicinal
products for both human and veterinary use. It introduced a transparent procedure for the development,
consultation, finalization and implementation of pharmaceutical guidelines. The drug approval process
in European countries is accomplished in two phases:
1. Clinical trial.
2. Marketing authorization.
A clinical trial application (CTA) is filed to the competent authority of the state to conduct the clinical
trial within European Union (EU). The competent authority of that member state evaluates the
application. The clinical trials are conducted only after the approval. Marketing authorization
application is filed only after all the three phases of clinical trials are completed.
Europe has multiple structures and administrative procedures for obtaining market authorization of
pharmaceuticals. There are four different routes in the European Union to obtain marketing approval of
pharmaceuticals.

48
Centralized Procedure
The centralized procedure is one which allows applicants to obtain a marketing authorization that is
valid throughout the EU. In this procedure, applications are accepted with regards to products of bio-
technological sciences and New Chemical Entities (NCEs). All the Biotechnological products are

marketing authorization is valid for entire European Union. The EMEA staff, on receiving the
Marketing Authorization Approval (MAA), checks the completeness and compliance of the application
with EU guidelines. This appraisal must be completed within ten days from the date of filing the
application. The sponsor pays the appropriate fees. Then, EMEA has 210 days to consider the
application. It can appoint rapporteurs, who assess the application and report Committee for Medicinal
Products for Human Use (CHMP). CHMP gives an opinion whether to accept or reject the application;
it is forwarded to the European Commission, which can take 90 days to arrive at a decision. The total
time for approval is around 300 days (210+90). Under this product is recognized by all member
countries through a single application to EMA. Example: CEP submissions, eDMF, CTD submission
on special product such as all Orphans Medicinal Product. All biotechnology based product, Specified
Aids and cancer Medicines, Specified Antiviral Medicines, Specified Medicines for Neurodegenerative
Disorder including diabetes and Specified Medicines for Auto immune Diseases/dysfunctions. The
rejection of application under these schemes bans entry to EU.
in a single authorization valid in EU, Norway, Iceland and Liechtenstein

approval.
Centralized process is compulsory for:

those medicines which are intended for the treatment of Cancer, HIV/Aids, diabetes,
neurodegenerative disorders or autoimmune diseases and other immune dysfunctions.

49
 Decentralized Procedure

as very efficient procedure. Decentralized procedure is followed to obtain marketing authorizations in

several member states. The sponsor submits to a national regulatory authority, the application and a list
of all Concerned Member States (CMSs), specifying a Reference Member State (RMS). The RMS must
validate the application and Summary of Product Characteristics (SPCs); prepare a draft assessment
report within 210 days and send a copy to the CMSs; this report can be approved within 90 days. If a

50
medicinal product is supposed to cause potential serious risk to public health, CMSs can raise any
objections and then the CHMP intervenes and takes a final decision within 30 days. However, a
negative decision can affect the registration in many countries under this scheme also following
product cannot be registered: Orphans Medicinal Product, All biotechnology based product, Specified
Aids and Cancer Medicines, Specified Antiviral Medicines, Specified Medicines for
Neurodegenerative Disorder including diabetes and Specified Medicines for Auto immune
Diseases/dysfunctions .

51
National Procedure
In Europe each nation has its own regulatory body. National procedure is procedure adopted by each
nation independently of other nations. The fees are affordable even for small firms. It saves on
translation cost to English or regional languages. It creates a base for Mutual recognition Procedure
Biotechnical procedures cannot be registered through national procedure. The Centralized filing
through EMA is compulsory for the same. The application, submitted by the sponsor under the national
rules to the national competent authority, is reviewed and a marketing authorization is granted. Under
this scheme also following product cannot be registered: Orphans Medicinal Product, All
Biotechnology Based Product, Specified Aids and Cancer Medicines, Specified Antiviral Medicines,
Specified Medicines for Neurodegenerative Disorder including diabetes and Specified Medicines for
Auto immune Diseases/dysfunctions.

52
 Unit III

CMC Chemistry, Manufacturing and Controls:

The Chemistry, Manufacturing, and Controls (CMC) includes manufacturing of bulk drug substance
and final drug product, setting specifications, release criteria, stability programs, and analytical
methods. All stages of the drug development life cycle after drug discovery involve CMC. During
preclinical drug development, the proper analytical methods are validated to monitor the product.
Stability testing may be initiated, the physicochemical properties of the product are determined; raw
materials are chosen and tested. When the drug development process moves into the clinical stage,
further analytical method validation is required, and additional characterization of the drug product is
needed. After clinical trials the scale up process must ensure that the larger batches of product are the
same and meet the same specifications as the drug tested in the clinical trials. After the manufacturing
process is qualified, lot release and in process testing will continue to take place. The Chemistry,
manufacturing and controls (CMC) section is a very important part of a pharmaceutical clinical trial or
marketing application. There have been cases of pharmaceuticals being denied approval
because the quality of the product and the manufacturing process was not shown to be of a sufficiently
high standard.
Regulators need to be assured that there is consistency between the product tested
during the clinical trials and commercialization batches produced years later. The ICH and FDA has
provided several guidance documents designed to help pharmaceutical companies with the CMC
expectations of their product. These include:
i.

ii. ICH Q2(R1) Validation of Analytical Procedures: Text and Methodology

iii. ICH Q3C(R6) Impurities: Residual Solvents
iv. ICH Q6A Specification: Test Procedures and Acceptance Criteria for New Drug Substances and
v. New Drug Products: Chemical Substances
The amount of CMC information needed varies according to other clinical trial factors such as size,
duration, dosage form and prior usage. ICH Q6A breaks down the required CMC tests into two
categories: Universal tests which are applicable to all new drug substances or drug products and
specific tests which are tests that can be considered on a case by case basis. To be clear on the
definitions, drug substance is the unformulated active substance while the drug product is the final
product once formulated with excipients.
53
CMC Universal Tests New Drug Substance
Description
A statement about the physical state of the drug substance (solid, liquid, ect.) and color.
Identification
Tests those are specific for identification of new drug substance. If the product is optically active there
may be a need for chiral assay. A stability indicating procedure should be included.
Impurities
The drug substance must be tested for impurities, including organic and inorganic impurities and
residual solvents.
CMC Universal Tests New Drug Product
Description
A description of the dosage form (size, shape and color).
Identification
Identity tests should establish the identity of the drug product. These tests should be able to
discriminate between compounds of closely related structure which are likely to be present. Stability
indicating assays to determine strength should be included.
Impurities
The drug product must be tested for impurities, including organic and inorganic degradation products
and residual solvents.
CMC Specific Tests New Drug Substance
Physicochemical Properties
Common tests for physicochemical properties include pH, melting
point, solubility, pKa, hygroscopicity, X-ray diffraction, viscosity, osmolality, partition coefficient and
refractive index.
Particle Size
Drug substances intended for use in solid or suspension products should have
testing for particle size distribution carried out. Particle size can have an effect on dissolution
rates, bioavailability and stability.
Polymorphic Forms
Some drug substances exist in different crystalline forms which will have
different physical properties. Differences in these forms could affect the performance of the
drug. If different forms exist and affect the drug, then the appropriate solid state should be
specified.
54
Chiral Assays
For chiral drug substances which are developed as a single enantiomer, control of
the other enantiomer should be considered in the same manner as for other impurities. Identity
tests should be capable of distinguishing both enantiomers.
Water Content
When the drug substance is known to be hygroscopic or degraded by moisture it is important to
perform water content testing. The Karl Fischer method is preferred over loss on drying procedures.
Inorganic Impurities
Based on the manufacturing process there may be a need to test for inorganic impurities.
Microbial testing
Sterile drugs will need to be tested for sterility and the level of endotoxins
may be needed to be tested if the product is injectable. Microbial limits testing, which is a
measure of the bioburden on the product and also tests for the absence of objectionable
organisms, may be used to test nonsterile products.

CMC Specific Tests New Drug Products

These tests are dependent of the dosage form of the new drug product. The following dosage forms will
be addressed in the table below: solid oral tablets and hard capsules, liquid oral including powders that
are intended for reconstitution as oral liquids, and parenterals.

55
Regulation of Combination Products and Devices
A combination product is a product composed of any combination of a drug and a device; a biological
product and a device; a drug and a biological product; or a drug, device, and a biological product.
Under 21 CFR 3.2 (e), a combination product is defined to include:
I. A product comprised of two or more regulated components (i.e., drug/device, biologic/device,
drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined
-
product];
II. Two or more separate products packaged together in a single package or as a unit and
comprised of drug and device products, device and biological products, or biological and drug
-
III. A drug, device, or biological product packaged separately that according to its investigational
plan or proposed labeling is intended for use only with an approved individually specified drug,
56
 device, or biological product where both are required to achieve the intended use, indication, or
effect and where, upon approval of the proposed product, the labeling of the approved product
would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route
of administration, or significa -
combination product]; or
IV. Any investigational drug, device, or biological product packaged separately that according to its
proposed labeling is for use only with another individually specified investigational drug,
device, or biological product where both are required to achieve the intended use, indication, or
-
Examples of single-entity combination products (where the components are physically, chemically or
otherwise combined) (21 CFR 3.2(e)(1)):
Monoclonal antibody combined with a therapeutic drug
Device coated or impregnated with a drug or biologic
a) Drug-eluting stent, pacing lead with steroid-coated tip, catheter with antimicrobial coating,
condom with spermicide, transdermal patch
Prefilled drug delivery systems (syringes, insulin injector pen, metered dose inhaler)
Examples of co-packaged combination products (the components are packaged together) (21 CFR
3.2(e)(2)):
Drug or vaccine vial packaged with a delivery device
Surgical tray with surgical instruments, drapes, and anesthetic or antimicrobial swabs
First-aid kits containing devices (bandages, gauze), and drugs (antibiotic ointments, pain
relievers)
Example a of product that may be cross-labeled combination products (components are separately
provided but specifically labeled for use together) (21 CFR 3.2(e)(3) or (e)(4)):
Photosensitizing drug and activating laser/light source
Regulation of combination products
The Office of Combination Products (OCP) broadly responsible for overseeing the regulation of
combination products, or products that involves components that would normally be regulated under
different FDA Centers. The Office of Combination Products ensures the efficiency and timeliness of
the procedures that make these important products available to patients. The roles of the Office of
Combination Products (OCP) include:
a) To develop guidance and regulations to clarify the regulation of combination products.

57
 b) To classify medical products as drugs, devices, biological products or combination products and
assign them to an FDA center for premarket review and regulation, where their classification or
assignment is unclear or in dispute.
c) To ensure timely and effective premarket review of combination products by overseeing the
timeliness, alignment of coordination of reviews involving more than one agency center,
including through monitoring and management of the intercenter consult process
d) To ensure consistent and appropriate postmarket regulation of combination products.
e) To resolve disputes regarding the timeliness of premarket review of combination products.
The Director of OCP is a member of the FDA Combination Products Policy Council.
Review of combination products
Combination products are assigned to a FDA center that will have primary jurisdiction for its
premarket review and regulation. Consistent with section 503(g)(1) of the Act, assignment to a center
with primary jurisdiction for premarket review and post-market regulation, or a lead center, is based on
example, if
the PMOA of a device-biological combination product is attributable to the biological product, the
Agency component responsible for premarket review of that biological product would have primary
jurisdiction for the combination product. Sectio
mode of action of a combination product that provides the most important therapeutic action of the
t 21 CFR 3.2
Is an IND/IDE needed for combination products?
One investigational application is generally sufficient for a combination product. That application
should include all information on the entire combination product. For example, if the investigation is
for a drug-device combination product, the application should include the details on the drug and
device that typically would be submitted in an investigational new drug application (IND) and
investigational device exemption application (IDE), respectively. Typically, an IND is submitted if the
combination p

What types of marketing applications are required for a combination product?

Combination products are typically marketed under a marketing authorization type associated with the
constituent part that provides the primary mode of action (PMOA) for the combination product (i.e., a
new drug application (NDA) or abbreviated new drug application (ANDA) if it has a drug PMOA, a
biologic license application (BLA) if it has a biologic PMOA, or a premarket approval application

58
 marketing application is generally sufficient for a combination product. In some cases, however, a
sponsor may wish to submit separate marketing applications for different constituent parts of a
combination product, and FDA may consider this permissible.

CTD & eCTD formats

The Common Technical Document (CTD) is a set of specifications for an application dossier for the
registration of Medicines and designed to be used across Europe, Japan and the United States. It is an
internationally agreed format for the preparation of applications regarding new drugs intended to be
submitted to regional regulatory authorities in participating countries. It was developed by
the European Medicines Agency (EMA, Europe), the Food and Drug Administration (FDA, US) and
the Ministry of Health, Labour and Welfare (Japan). The CTD is maintained by the International
Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for
Human Use (ICH). The Common Technical Document is divided into five modules:
1. Administrative and prescribing information
2. Overview and summary of modules 3 to 5
3. Quality (pharmaceutical documentation)
4. Preclinical (Pharmacology/Toxicology)
5. Clinical efficacy and safety (Clinical Trials)

After the United States, European Union and Japan, the CTD has been adopted by several other countries
including Canada and Switzerland. Although CTD as a standard was able to harmonize and offer a better
submissions format, it also brought along challenges of managing and maintaining huge volumes of

59
paper based documentation both for health authorities and companies. With the aim of overcoming the
challenge of managing huge volumes of paper based product data and to enable faster and efficient
submissions, an electronic equivalent of CTD was introduced as Electronic Common Technical
Document (eCTD).
Electronic Common Technical Document (eCTD) is the submission of (mostly) PDF leaf documents,
stored in the eCTD directory structure, crucially accessed through the XML backbone (index.xml) and
with the files integrity guaranteed by the MD5 Checksum. It also provisions multilingual and multi-
region aspects of submission process. Apart from this the lifecycle for submission procedure also got
categorized into three simple steps:
a) New or initial submission
b) Updates
c) Re-submission only for what has been changed
The eCTD is the standard format for submitting applications, amendments, supplements, and reports to

Research (CBER). Following submission can be made through eCTD formats:

a) New Drug Application (NDA)
b) Abbreviated New Drug Application (ANDA)
c) Investigational New Drug Application (IND)
d) Biologics License Application (BLA)
e) Master files: Drug Master File (DMF) and Biologics Master File (BMF)
f) Emergency Use Authorization (EUA)
Electronic submissions make it easier for FDA to review data, approve new drugs, and monitor drugs
after they go on the market. Using eCTD also simplifies the process for submitters, because it is the
same format used by drug regulatory agencies in other countries.

Industry and FDA liaison

Who is FDA?
The U.S. Food and Drug Administration (FDA) is responsible for protecting the public health by
ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and
medical devices; and by ensuring the safety of nation's food supply, cosmetics, and products that emit
radiation. FDA fulfills this responsibility by ensuring the security of the food supply and by fostering
development of medical products to respond to deliberate and naturally emerging public health threats.

60
The Food and Drug Administration is divided into many centers, each center comprising a division
with specific regulatory responsibilities. The following are the main centers:
CDER Center for Drug Evaluation and Research
CBER Center for Biologics Evaluation and Research
CDRH Center for Devices and Radiologic Health
CFSAN Center of Food Safety and Applied Nutrition
CVM Center for Veterinary Medicine
NCTR National Center for Toxicological Research
Why Industry/FDA liaisoning is required?
Government regulation of the Pharmaceutical industry is a significant factor in the development and
marketing of drug products. In view of the constantly changing rules and regulations established by the
FDA, and its role in monitoring the progress and development of new compounds, the need for
effective liaison between the FDA and industry is evident. Experienced Drug Regulatory Affairs
(DRA) personnel are essential in the process of new product development. They are largely responsible
for establishing a liaison with their counterparts at the U.S. Food and Drug Administration (FDA) and
other regulatory agencies globally.
Industry/ FDA conferences, in which information is freely exchanged beginning prior to submission of
an IND and continuing throughout the life of the drug, are essential to achieving any degree of
successful liaison. Industry personnel must have a clear understanding of what FDA expects in support
of manufacturing control procedures, safety and efficacy. On the other hand, FDA must have a clear
understanding of all data available regarding a particular compound or product. Early meetings prior to
IND submission establish the atmosphere under which future meetings will be conducted. Preclinical
data and plans for clinical studies should be discussed. FDA personnel present at these meetings
generally include a Consumer Safety Officer, a Medical Officer, a Pharmacologist, a Chemist and,
when necessary, a Statistician. Those representing industry should be counterparts to these scientific
specialists, not Department Heads but rather those involved with the actual generation of data.
Following submission of the IND, industry personnel must attempt to keep FDA abreast of progress
through informative, concise progress reports. When a substantial amount of new data becomes
available, it is time for a second educational conference to review progress and discuss future work
required. Once we understand FDA's position in the review process and are willing to help reviewing
officers wherever possible, the review and approval process will proceed with little interruption and
arrive at a conclusion acceptable to both parties.

61
Proper liaison with FDA is not limited to the development of new products. It is needed and can be
highly effective in the day to day activities involving "New" and "Old" drugs, OTC Monographs, the
development and revision of old drug monographs, amendments, and supplements to NDA's. All
correspondence (letters, telephone or personal contacts) with the FDA is coordinated through the
Product Registration Office and reports are forwarded to the appropriate action personnel. Follow-up
action is initiated where necessary in order to assure timely response.
Industry/FDA meetings
All meetings with the FDA are held at the pleasure of the agency and should be requested judiciously.
Project managers, a large percentage of whom are former FDA field investigators, are responsible for
coordinating FDA/industry meetings. Their other duties include acting as the contact point between the
division and the regulated industry, preparing minutes of FDA/ industry meetings, and assisting the
division with the FDA advisory committee meetings. There are three types of meeting that industry can
request to the agency. These are typically known as Type A, B, or C meetings.
Type A meetings are considered the most important. These are meetings immediately necessary for a
delayed development program sometimes called a critical path meeting. Type A meetings are usually to
dispute issues that arise during new drug development, or to resolve clinical holds that the FDA has
deemed necessary, or at times they may pertain to protocol assessments after the FDA has critiqued the
submitted protocols. These meetings are usually scheduled 30 days from FDAs receipt of a written
request for a meeting. If the sponsors request a date beyond the 30 days, the meeting should occur no
later than 14 days after the date requested.
Type B meetings are those that usually occur for a pre-IND, an End of Phase 1 (EOP1), an End of
Phase 2 (EOP2), a Pre Phase 3, or a Pre-NDA or BLA. All of these meetings will be honored by the
FDA. These meetings are usually scheduled 60 days from the time the agency received the written
request. If the sponsor requests a date beyond 60 days, the meeting should occur no later than 14 days
after the date requested.
Type C meetings are any other meeting not falling into Type A or B meetings. These are meetings that
pertain to the review of human drug applications. These meetings are usually scheduled within 75 days
of the agencies of the written request. If a sponsor requests a date beyond 75 days the meeting should
be scheduled to occur no later than 14 days after the date requested.
Pre-IND/Preclinical Meetings: Prior to clinical studies, the sponsor needs to demonstrate evidence
that the compound is biologically active, and both the sponsor and the FDA need data showing that the
drug is reasonably safe for initial administration to humans; hence the filing of an IND. Preclinical
meetings are occasionally conducted with the appropriate division that would review the IND or the
62
drug marketing application, and these meetings are typically requested by the sponsor of a drug.
Meetings at such an early stage in the process are sometimes useful opportunities for open discussion
about testing phases, data requirements, and any scientific issues that may need to be resolved prior to
IND submission. At these meetings, the sponsor and the FDA discuss and agree upon the design of the
animal studies needed to initiate human testing, and perhaps discuss the types of clinical testing that
would best demonstrate the safety and efficacy of the drug in humans.
End-of-Phase 2 Meeting (EOP2): -of-
whether it is safe to begin phase 3 testing. This is also the time to plan protocols for phase 3 human
studies and to discuss and identify any additional information that may be required to support the
submission of an NDA. It is also intended to establish an agreement between the agency and the
sponsor of the overall plan for phase 3 and the objectives and design of particular studies. These
meetings avoid unnecessary expenditures of time and money because data requirements have been
clarified. One month before the end-of-phase 2 meeting, the sponsor should submit the background
information and summary protocols for phase 3 studies. This information should include data
supporting the claim of the new drug product, chemistry data, animal data and proposed additional
animal data, results of phase 1 and 2 studies, statistical methods being used, specific protocols for
phase 3 studies, as well as a copy of the proposed labeling for the drug, if available. This summary
provides the review team with information needed to prepare for a productive meeting.
End-of-Phase 2 Conference: When a firm has reached the end of phase 2, it should contact the
appropriate division at the FDA to arrange for a conference. All clinical data should be summarized,
tabulated, and statistically analyzed, as described. These data, together with any additional preclinical
and manufacturing and controls data, and plans and protocols for phase 3 should be submitted at least 1
month in advance of the scheduled meeting. A copy containing only clinical data, as a rule, plus the
proposed protocols for phase 3, should be provided for the FDA statistician. The submission also
should include any specific questions the firm wishes to discuss.
Pre-NDA Meetings: The purpose of a pre-NDA meeting is to discuss the presentation of data (both
paper and electronic) in support of the application. The information provided at the meeting by the
sponsor includes: - A summary of clinical studies to be submitted in the NDA; The proposed format for
organizing the submission including methods for presenting the data; and other information that needs
to be discussed.
The meeting is conducted to uncover any major unresolved problems or issues; to identify studies the
sponsor is relying on as adequate and well controlled in establishing the effectiveness of the drug; to
help the reviewers to become acquainted with the general information to be submitted; and to discuss
63
the presentation of the data in the NDA to facilitate its review. Once the NDA is filed, a meeting may
also occur 90 days after the initial submission of the application to discuss issues that are uncovered in
the initial review.
Advisory Committee Meetings:
technical committees. Advisory committees have been established to advise and make

advisory committees is to provide independent expert scientific advice to the agency in its evaluation of
regulated products, and to help make sound decisions based on the reasonable application of good
science. The committees are advisory in nature, and final decisions are made by the FDA. They consist
of individuals with recognized expertise and judgment in a specific field who have the training and
experience necessary to evaluate information objectively and to interpret its significance under various,
often controversial, circumstances. Advisory committees weigh available evidence and provide
scientific and medical advice on the safety, effectiveness, and appropriate use of products under FDA
jurisdiction. Another role is to advise the agency on general criteria for evaluation and on broad
regulatory and scientific issues that are not related to a specific product. Although advisory committees
have a prominent role in the product approval stage, they are sometimes used earlier in the product
development cycle and may be invited to consider post-marketing issues.

International Council for Harmonization of Technical Requirements for Pharmaceuticals for

Human Use (ICH) Guidelines
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for
Human Use (ICH) was created in 1990 and brings together regulatory and pharmaceutical industry
authorities to discuss scientific and technical aspects of drug registration and development.

high-quality medicines are developed and registered in the most resource-efficient manner. Greater
uniformity can be achieved through the creation of ICH Guidelines through a process of scientific
consensus with regulatory and pharma industry experts working side-by-side.
ICH guidelines are provided for:
Quality guidelines: Quality area include pivotal milestones such as the conduct of stability studies,
defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical
quality based on Good Manufacturing Practice (GMP) risk management.
Safety guidelines: A comprehensive set of ICH guidelines that help identify potential risks, such as
carcinogenicity, genotoxicity and reprotoxicity. An example is a non-clinical testing strategy for
64
evaluating the QT interval prolongation liability, the single most important cause of drug withdrawals
in recent years.
Efficacy guidelines: Efficacy guidelines concerned with the design, conduct, safety and reporting of
clinical trials. It also covers novel types of medicines derived from biotechnological processes and the
use of pharmacogenetics/genomics techniques to produce better targeted medicines.
Multidisciplinary guidelines:
Safety or Efficacy guidelines, and includes the ICH medical terminology (MedDRA), the Common
Technical Document (CTD), and the development of Electronic Standards for the Transfer of
Regulatory Information (ESTRI).

ICH Quality guidelines

ICH Guidelines incorporate a variety of quality guidances to evaluate pharmaceutical products that
include stability analysis, an evaluation of impurities and quality risk management:
Stability (Q1A-Q1F)
Q1A (R2) Stability Testing of New Drug Substances and Products: This guidance is for analyzing
the product to determine its stability in a variety of environmental conditions.
Q1B Stability Testing: Photo stability Testing of New Drug Substances and Products: Also, for
stability testing, this guideline studies the effect of light on pharma products.
65
Q1C Stability Testing for New Dosage Forms: This is an annex to the ICH Harmonized Tripartite
Guideline on Stability Testing for New Drugs and Products.
Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products:
This applies to stability testing of a product using bracketing and matrixing.
Q1E Evaluation for Stability Data: This section addresses the method of evaluation of data after the
analysis of drug products for stability testing.
Q1F Stability data package for registration in climatic zones III and IV - explanatory note.
Analytical validation
Q2 (R1) Validation of analytical procedures: text and methodology
Q2 (R2)/Q14 Analytical procedure development and revision of Q2 (R1)
Impurities
Q3A (R2) Impurities in new drug substances
Q3B (R2) Impurities in new drug products
Q3C (R6) Residual solvents
Q3D Elemental impurities
Regulatory acceptance
ICH Q4A-Q4B Pharmacopoeias
Quality of biotechnological products
ICH Q5A-Q5E Quality of biotechnological products
Specifications
ICH Q6A-Q6B Specifications
Good manufacturing practice
Q7 Good manufacturing practice for active pharmaceutical ingredients
Pharmaceutical development
Q8 (R2) Pharmaceutical development
Q9 Quality risk management
Q10 Pharmaceutical quality system
Q11 Development and manufacture of drug substances (chemical entities and
biotechnological/biological entities)
Lifecycle management
ICH Q12 Technical and regulatory considerations for pharmaceutical product lifecycle management
Continuous manufacturing of Drug substances and drug product
Q13 Continuous manufacturing of Drug substances and drug product
66
Analytical procedure development
Q14 Analytical procedure development

ICH Safety guidelines

67
ICH Efficacy Guidelines

ICH Multidisciplinary Guidelines

68
ICH Stability Guidelines
Stability Testing of New Drug Substances and Products Q1A (R2)
The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug
product varies with time under the influence of a variety of environmental factors such as temperature,
humidity, and light, and to establish a retest period for the drug substance or a shelf life for the drug
product and recommended storage conditions.
Drug Substance
Information on the stability of the drug substance is an integral part of the systematic approach to
stability evaluation.
Stress testing: Stress testing of the drug substance can help identify the likely degradation products,
which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and
validate the stability indicating power of the analytical procedures used. The nature of the stress testing
will depend on the individual drug substance and the type of drug product involved. Stress testing is
likely to be carried out on a single batch of the drug substance. It should include the effect of
temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity
(e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The
testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of
pH values when in solution or suspension. Photo stability testing should be an integral part of stress
testing.
Selection of Batches: Data from formal stability studies should be provided on at least three primary
batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the
same synthetic route as, and using a method of manufacture and procedure that simulates the final
process to be used for, production batches. The overall quality of the batches of drug substance placed
on formal stability studies should be representative of the quality of the material to be made on a
production scale.
Container Closure System: The stability studies should be conducted on the drug substance packaged
in a container closure system that is the same as or simulates the packaging proposed for storage and
distribution.
Specification: Stability studies should include testing of those attributes of the drug substance that are
susceptible to change during storage and are likely to influence quality, safety, and/or efficacy. The
testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes.
Validated stability-indicating analytical procedures should be applied. Whether and to what extent
replication should be performed will depend on the results from validation studies.
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Testing Frequency: For long term studies, frequency of testing should be sufficient to establish the
stability profile of the drug substance. For drug substances with a proposed re-test period of at least 12
months, the frequency of testing at the long term storage condition should normally be every 3 months
over the first year, every 6 months over the second year, and annually thereafter through the proposed
re-test period. At the accelerated storage condition, a minimum of three time points, including the
initial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an
expectation (based on development experience) exists that results from accelerated studies are likely to
approach significant change criteria, increased testing should be conducted either by adding samples at
the final time point or by including a fourth time point in the study design. When testing at the
intermediate storage condition is called for as a result of significant change at the accelerated storage
condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12
months), from a 12- month study is recommended.
Storage Conditions: In general, a drug substance should be evaluated under storage conditions that
test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the
lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use. The long

time of submission and should be continued for a period of time sufficient to cover the proposed re-test
period. Additional data accumulated during the assessment period of the registration application should
be submitted to the authorities if requested. Data from the accelerated storage condition and, if
appropriate, from the intermediate storage condition can be used to evaluate the effect of short term
excursions outside the label storage conditions (such as might occur during shipping).

its specification.

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Data from refrigerated storage should be assessed according to the evaluation section of this guideline,
except where explicitly noted below:

ition, the
proposed re-test period should be based on the real time data available at the long term storage

condition, a discussion should be provided to address the effect of short term excursions outside the
label storage condition, e.g., during shipping or handling.
For drug substances intended for storage in a freezer, the re-test period should be based on the real time
data obtained at the long term storage condition. In the absence of an accelerated storage condition for
drug substances intended to be stored in a freezer, testing on a single batch at an elevated temperature
(e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the
effect of short term excursions outside the proposed label storage condition, e.g., during shipping or
handling.

Evaluation: The purpose of the stability study is to establish, based on testing a minimum of three
batches of the drug substance and evaluating the stability information (including, as appropriate, results
of the physical, chemical, biological, and microbiological tests), a re-test period applicable to all future
batches of the drug substance manufactured under similar circumstances. The degree of variability of
individual batches affects the confidence that a future production batch will remain within specification
throughout the assigned re-test period.
Statements/Labeling: A storage statement should be established for the labeling in accordance with
relevant national/regional requirements. The statement should be based on the stability evaluation of
the drug substance. Where applicable, specific instructions should be provided, particularly for drug

71
substances that cannot t
should be avoided. A re-test period should be derived from the stability information, and a retest date
should be displayed on the container label if appropriate.
Drug Product
The design of the formal stability studies for the drug product should be based on knowledge of the
behavior and properties of the drug substance and from stability studies on the drug substance and on
experience gained from clinical formulation studies. The likely changes on storage and the rationale for
the selection of attributes to be tested in the formal stability studies should be stated.
Photo stability Testing: Photo stability testing should be conducted on at least one primary batch of
the drug product if appropriate. The standard conditions for Photostability testing are described in ICH
Q1B.

If long-
condition, additional testing at the
intermediate storage condition should be conducted and evaluated against significant change criteria.
-month study at the
intermediate storage condition.

1. A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency
when using biological or immunological procedures;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g.,
color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some
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changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected
under accelerated conditions;
And, as appropriate for the dosage form:
4. Failure to meet the acceptance criterion for pH; or
5. Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Drug products packaged in semi-permeable containers

Aqueous-based products packaged in semi-permeable containers should be evaluated for potential
water loss in addition to physical, chemical, biological, and microbiological stability. This evaluation
can be carried out under conditions of low relative humidity, as discussed below. Ultimately, it should
be demonstrated that aqueous-based drug products stored in semi-permeable containers can withstand
low relative humidity environments. Other comparable approaches can be developed and reported for
non-aqueous, solvent-based products.

A 5% loss in water from its initial value is considered a significant change for a product packaged in a
semi-
for small containers (1 mL or less) or unit dose products, a water loss of 5% or more after an equivalent
appropriate, if justified.

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Mutual Recognition Procedure (MRP)
Under this a product registered in one country is mutually recognized by the other country. The
application is required to make application only once for initial registration. The same application with
some regional changes is accepted by another member country. Assessment Report of medicinal
Product by Member Countries in EU: During Mutual recognition process the assessment report of
Reference member state is reviewed before granting approval. The submission can be made to any
number of the other member states and the RMS sends a copy of the assessment report to the CMSs,
who can raise any objections within 90 days. Each CMS issues a national marketing authorization with
an identical SPC. Under this scheme following product cannot be registered: Orphans Medicinal
Product, All biotechnology based product, Specified Aids and cancer Medicines, Specified Antiviral
Medicines, Specified Medicines for Neurodegenerative Disorder including diabetes and Specified
Medicines for Auto immune Diseases/ dysfunctions.
Drug Approval Process in United Kingdom
The medicines and healthcare products regulatory agency (MHRA) regulate medicines, medical
devices and other medical products for their approval in the United Kingdom. Any medicinal agent to
be marketed in the United Kingdom has to follow the guidelines and regulations framed by MHRA, a
regulatory authority which approves the drug products. By knowing the requirements of the MHRA
guidelines and regulations, it is easy for a product to get into the UK market. The agency protects and
improves public health and supports all the innovations through scientific research and development
programs. The agency has three centers:

public health with the help of NHS clinical data.

a worldwide pioneer in
maintaining the standards and Control of biological products.

body for medicines, medical devices and blood transfusion and furthermore in charge of guaranteeing
the wellbeing, quality and viability of pharmaceuticals.
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Functions of MHRA

Types of MHRA licenses:

1. Pharmaceutical manufacturers
2. Import of medicines
3. Biological compounds and chemical compounds
How to license a medicine for sale in UK
License for sale of a drug can be done by different procedures:
a) National procedure: This procedure is used when the drug has to be marketed only in the UK. A
5-digit company number and a PL number is to be obtained in the being of the procedure. The
application process takes about 210 days. The entire dossier and the informed consent checklist
should be submitted, if the applicant is making an application for an informed consent
marketing authorization.
b) Centralized procedure: It is required when the drug manufactured is to be marketed throughout
Europe. All the new substance that is produced will take a single license when the substance has
to be marketed in all European states as well as Norway, Iceland and Liechtenstein.
c) Decentralized procedures (DCP): It is needed if the drug has to be manufactured and marketed
in the UK and other European countries.

Member State. The other state to which a manufacturer wants to apply is called Concerned Member
States (CMS). A DCP submission date should be booked if applicant wish applies for the Reference
Member State (RMS). The reply from MHRA is obtained within 24 hours after confirming of booking.
Product license (PL) number and the DCP number will be issued along with the reply. MHRA acts as
RMS to another member state, that applicant has planned to apply (CMSs). It takes up to 210 days for
the procedure, excluding the time taken for submission of further data and information required. If the

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application is approved then the MHRA and the CMS will issue a national license for the product to
market within 30 days of the approval granted.
d) Mutual recognition procedure (MRP): If drug already has a marketing license in at least one or
more European countries but want to market the drug in any other countries, this license is
applied.
The MHRA verify whether the item can be acknowledged for mutual recognition procedure and issue
MRP number which is to be utilized as a part of the application. After the issue, the MHRA acts as
RMS and will lead the assessment of the application. The processing of the application takes about 90
days. If the application is approved then the national license will be issued within 30 days by the CMS.

How does MHRA classify the medicine or medical device?

Some substances are difficult to be classified as medicines or medical devices example in the case of
cosmetics biocidal products, herbal products, medical devices, laboratory and machinery equipment,
food products etc. Such products are called a Borderline product.
Borderline medicines
The MHRA checks whether the active ingredient in the given product has the medicinal property for
treating or preventing diseases in human being in order to consider it as medicine. If any substance or
combination of substance is administered to a human being for the purpose of restoring, modifying and
correcting a physiological function then it is considered as borderline medicine. Food supplements like
vitamins, minerals and amino acids are considered as food safety and food labelling legislation rather
than medicines control. The MHRA confirms whether the active substance present would regard to
whether the product is a medicinal product or not.
MHRA decides whether a product is a medicine when a manufacturer comes with the product for
advice or when the drug is marketed in the name of medicine.
Fast tracking of marketing authorization
Quick track of utilization should be possible if there is confirmation to demonstrate that item would
give a noteworthy breakdown in treatment conditions. No additional fee is charged for fast-tracking of
applications. Following are the categories for which fast track application will
be applicable:
seases for which current treatment is ineffective or inadequate.
-threatening and severe disease for which present treatment is ineffective or inadequate.
current
treatment.
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To get fast track application then a requisition letter of not more 3 pages should be mailed to
[email protected]. The letter must incorporate the classification of ailment, a concise portrayal of
major clinical properties of the medicinal agent, confirm for the advantages of the item for the
proposed signs.
Types of application
- Article 8(3)
s - Article 10
- Article 10a
- Article 10b
- Article 10c
Abridged application procedure can be used in a certain application where pre-clinical and clinical
studies are not needed. The types of application that can be used in this route are generic/ biosimilars
(Article 10), informed consent (Article 10c) and well established use (Article 10 a) application. The
legal basis for all types of application is set out in Directive 2001/83/EC and also in Regulation (EC)
No726/2004.
Application process
Electronic common technical documentation method is used for the submission of application. In case
if the applicant cannot submit by this method, non-electronic submission (NeeS) is also acceptable.
MHRA checks whether the NeeS and e CTD are technically valid using the ExtendoEurs tool
validation. If the applicant has any questions regarding the submission of the application to be asked
then that can be mailed to [email protected].
Active substance master files (ASMFs)
Active substance master file holders should submit their dossier to MHRA. Applicant must submit his
active substance master file before the application being submitted or along with the submission of the
application. If the active substance master file is not submitted then the application will not be valid
unless the dossier of the active substance is submitted. ASMF holder will have to register with the
Common European Submission Platform (CESP) and then will have to submit their application through
CESP.
Summary of product characteristics (SPC)
Using SPC (summary of product characteristic) template the manufacturer should submit a summary of
the product characteristic to MHRA in the proper format using MS Word Document (36KB).

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Ways to make a submission
Via Central European System Platform (CESP) manufacturer can submit the application. From January
2016, it is mandatory to submit electronic application forms (eAFs) for new marketing authorization,
renewal and variation application submissions. This application submission is same for all the
procedures (centralized, national or decentralized procedures). If submission of application is through
portal way, then both portal form, as well as eAFs, should be submitted. If the application is submitted
through CESP then, only eAFs submission is required.

Drug Approval Process in Australia

In Australia, all medicines must be approved for sale by the Therapeutic Goods Administration (TGA),
a division of the Australian Government Department of Health. Manufacturers of prescription
medicines usually also apply for the medicine to be subsidized under the Pharmaceutical Benefits
Scheme (PBS), under which the government pays some of the cost of medicines for patients.

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 Unit-V

Clinical Trials

A clinical trial is a research project that compares two or more treatments in patients with a particular
condition or at risk of a condition to help generate high quality evidence about which is the more
effective treatment or preventative strategy. The treatment being investigated in a clinical trial can be a
medicinal product, a procedure, a device or another type of therapeutic intervention. Clinical trials are
an essential part of the process of evidenced based practice and can help guide treatment decisions for
both health care professionals and patients. Clinical trials are an important part of the pathway by
which new medicinal products can obtain a license from MHRA and become available for use as a new
treatment in patients.
Why are clinical trials important?
Clinical trials are the best way to compare different approaches to preventing and treating illness and
health problems. Health professionals and patients need the evidence from trials to know which
treatments work best. Without trials, there is a risk that people could be given treatments which have no
advantage, waste resources and might even be harmful. Many treatments that are now in common use
in health care were tested in clinical trials. Some types of clinical trial are designed to look at a
treatment at an early stage of its development. Researchers and regulators will look at the information
they have gathered and decide whether it is safe and appropriate to continue the development of that
treatment. If the treatment has no benefit or has serious side effects, it may not be developed further.
How are trials set up?
Clinical trials are designed by doctors and other specialists with input from a wide variety of people,
increasingly including patients. They work together to decide what questions need to be answered. First
of all they look carefully at the results of the trials that have already been done to find out what is
already known. This is called a systematic review. A systematic review provides more accurate
answers than individual trials and also helps to identify important questions that still need to be
answered through further research. Doctors, nurses, patients and researchers work together with
statisticians, trial managers and representatives from pharmaceutical companies if relevant, to design
the best possible trial. The design for the trial forms the basis of the trial protocol.
When the trial protocol is ready it is sent to a research ethics committee, an independent group of
people that includes doctors, nurses, other medical staff, members of the public and sometimes lawyers.
They decide whether the trial is ethical. In particular they check whether:
the potential benefits of a new treatment are likely to outweigh the side effects
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 the information provided to help people to decide whether they want to participate in a trial is
clear and satisfactory
the way in which people will be asked to take part in a trial (recruited) is appropriate
there will be compensation for people in the trial in the unlikely event that something goes
wrong
travel expenses will be offered to people who take part.
The trial can only go ahead when it has been approved by an ethics committee.
Who can take part in clinical trials?
All trials have guidelines about who can take part. These are called eligibility criteria. Eligibility
criteria are used to ensure that trials include the sort of people who may benefit from the treatment, and
to make sure that people who take part are not exposed to avoidable risks. This means that there may
not always be an appropriate or suitable clinical trial for you to take part in. The inclusion criteria help
the researchers to decide who can take part in the trial. Some trials only include people in a certain age
group, or of one sex, or at a particular stage of their illness. The exclusion criteria state who cannot take
part in the trial, For example, many drug trials do not allow pregnant women to take part as there may
be a risk to the unborn baby. People who are already taking particular medicines may also be excluded
as these may affect the trial treatment.
How are people recruited to a trial?
A clinical trial is often run in a number of different hospitals or health centers. The doctor or nurse who
asks you to take part in a clinical trial may not be the person who designed and set up the study,
especially if it is very large. However, they will have been fully briefed about the study before agreeing
to become involved. They can give you all the information you need and will be able to answer your
questions.
What are the risks and benefits of trials?
Clinical trials are carefully designed to minimize the risks and maximize the benefits to all who take
part, whatever treatment they receive. Some trials will have very little risk involved. However, the risks
of a trial may be greater when less is known about the treatment being tested. Before any drugs are first
given to people, they will have been developed in a laboratory and checked for safety in animals. In all
trials the treatment may cause side effects that doctors cannot predict and that you may not be
expecting. These may be unpleasant and very rarely can be life-threatening. You should be told
everything that the researchers know about any possible risks and side effects and why the trial is
necessary so that you can make an informed choice about whether to take part. The benefit to you of

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this extra attention is that any changes in your health, whether or not they are related to the treatment
you are having, are frequently picked up and acted upon earlier than if you were not in a trial.
However, some people find that the extra attention makes them worry more about their condition and

Types of Clinical trials

Controlled Clinical trials
Controlled trials are designed to compare different treatments. Most controlled trials compare a new
treatment with the standard or usual treatment by setting up two groups of people. One group, known
as the trial group or intervention group, are given the new treatment. The other group is given the
standard treatment and is known as the control group. In situations where there is no standard treatment
the control group may not be given any treatment at all or may be given a placebo. A placebo treatment
is designed to appear very similar to the treatment being tested. For example, in a drug trial the placebo
looks exactly like the real drug, but in fact it is
placebo and to the treatment being tested, researchers can tell whether the treatment is having any real
benefit. The control group is very important. Comparing the results of the control group with those of
the treatment group is the only way researchers can reliably find out whether any improvement seen
with the new treatment is really due to that treatment and not just due to chance.
Blind Clinical trials
In a blind trial, the participants are not told which group they are in. This is because if they knew which
treatment they were getting, it might influence how they felt or how they reported their symptoms.
Some trials are double blind, which means that neither the participants nor the doctors treating them
know which people are getting expectations
influencing the results of the trial. To prevent people from guessing which treatment they are getting,
all the treatments are made to look as similar as possible. For example, in a drug trial all the tablets will
look the same whether they are the new treatment or the standard treatment.
Randomized Clinical trials
Many trials are randomized. This means that people are allocated at random to the treatment groups in
the trial, usually by using a computer programme. This is done so that each group has a similar mix of
people of different ages, sex and state of health. If it were left to the doctor or patient to decide who
should get which treatment they might be influenced by what they know about their illness. Patients
who are more or less likely to respond to a new treatment might all go into one particular group. In that
situation, if one group did better that the other it would not be clear whether the difference was due to
the treatment or because the groups were different.
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If the people are allocated to the treatment groups at random, like will be compared with like. If one
group does better than the other, it is likely to be because of the treatment, as the two groups are very
similar in every other way.
Clinical trial Phages
Clinical trial phases are steps in the research to determine if an intervention would be beneficial or
detrimental to humans and include Phases 0, I, II, III, IV, and V clinical studies (Table 1). During
Phase 0, pharmacodynamics and pharmacokinetics are determined. Safety studies are evaluated during
Phase I, efficacy during Phase II, and confirmation of safety and efficacy during Phase III. Sentry
studies are done in Phase IV and comparative effectiveness research and community-based research in
Phase V. Although this sounds easy and straightforward, definitions and purposes of the different
phases become muddied and studies to determine if a therapy should be used in the general population
of patients may be complex and results difficult to interpret. Clinical trials may go so wrong that
unplanned changes in the population studied, end points or analysis plan must be made. Understanding
the basis of clinical trial phases will help researchers plan and implement clinical study protocols and,
by doing so, improve the number of therapies coming to market for patients.

Exploratory IND studies (also known as Phase 0 studies) are conducted early in clinical phase
studies and involve limited human exposure and have no therapeutic or diagnostic intent. Doses are
subtherapeutic and patients are monitored by the clinical researcher and involve about 10 study
is usually less than 1 week. Pharmacodynamics and
pharmacokinetics are studied. These trials are before the traditional dose escalation, safety, and
tolerance studies, do not replace the Phase I clinical trials and do not indicate whether a therapy has a
positive impact on the targeted pathology. These studies help in eliminating candidate therapies before
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they reach Phase I studies. These trials were developed to shorten the critical path for drug
development, to explore pharmacokinetic and pharmacodynamic to help
in accelerating identification of promising drugs, and to reduce development time and costs.
Limitations of these trials include lack of therapeutic intent, motivation of patients to participate, may
delay or exclude patients from other clinical trials that may have therapeutic intent, micro dosing
pharmacokinetics and relationship to therapeutic dose, and availability of sensitive analytical methods.
A Phase I clinical trial evaluates the best way to administer a drug, its frequency and dose, the
maximum tolerated dose (MTD), and side effects. Tolerability, pharmacokinetics, and
pharmacodynamics are evaluated. These studies determine, most importantly, if the treatment is safe.
Trials usually include 20 to 100 patients and are monitored by the clinical researcher. Doses are
increased if there are no severe side effects and patients are tested to determine if he or she is
responding to the therapy. These escalation dose studies are used to determine the best and safest dose
that can be administered and is a fraction of the dose that caused harm during animal testing.
Unnecessary exposure of subjects to sub therapeutic doses while maintaining safety and rapid accrual is
the primary goal of Phase I trials. Subjects, in most cases, are healthy volunteers although patients with
a certain disease may be required. Contract research organizations usually conduct these studies and
stipends may be given. Testing is usually sequential with data being reviewed after every patient or
small group of patients. Dose-toxicity and dose-efficacy curves are determined during this phase and
include single ascending dose trials (Phase IA), multiple ascending dose trials (Phase IB), and food
effect studies.
Phase I/II dose finding studies determine the most successful dose (MSD) which is the dose which
maximizes the product of the probability of seeing no toxicity together with the probability of seeing a
therapeutic response. While a Phase I clinical study focuses on determining the MTD, Phase II studies
evaluate potential efficacy and characterizes treatment benefit for the disease in a convincing manner.
The intervention is not presumed to have any therapeutic effect whatsoever. These studies are
performed on larger groups (100 to 300 subjects) and are designed to assess how well the drug works
and to continue safety assessments. Therapeutic doses which were determined during Phase I are
administered and patients are monitored by the clinical researcher. Trials are often conducted in a
multi-institution setting. Phase II may be divided into Phase IIA which are pilot clinical trials to
evaluate efficacy and safety in selected populations with the disease or condition to be treated,
diagnosed or prevented (objectives may be on dose-response, type of patient, frequency of dosing, or
other identifiers of safety and efficacy) and Phase IIB which are the most rigorous trials designed to
demonstrate efficacy. The development process usually fails during this Phase II when the drug is
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discovered not to work as planned or to have toxic effects. The Phase II design depends on the quality
and adequacy of Phase I studies. A vulnerable aspect of both phases is the type of patient enrolled.
Patients in Phase II trials generally have more exclusion criteria than those in Phase III trials. Case
series and randomized clinical trial designs have been used. Single stage and multi-stage Phase II
clinical trial designs are often developed on the basis that one endpoint is of interest. A commonly used
Phase II design is based on the work of Gehan, a version of a two-stage design.
Phase III trials are the full scale evaluation of treatment and are designed to compare efficacy of the
new treatment with the standard treatment. These are the most rigorous and extensive type of scientific
clinical investigation -
usually the most expensive and time-consuming of the trials. The trials may be difficult to design and
run. Large groups (100 to 3000 subjects) are recruited and trial designs have included randomized
controlled trials (parallel design), uncontrolled trials (single treatment), historical controls, no-
randomized concurrent trials, factorial designs, and group sequential designs. Patients are monitored by
the clinical researcher and personal physician. Phase III clinical trials may be divided into Phase IIIA
which are trials done after efficacy of the therapy is demonstrated but before regulatory submission of a
New Drug Application (NDA) or other dossier and Phase IIIB which are conducted after submission of
an NDA or other dossier but before approval and launch.
Upon authorization by the FDA, therapies determined to have proven safety, efficacy and quality may
be made available to the general population. Patients and their physicians have expectations of benefit.
However, not all safety or efficacy issues have been determined. The FDA requires continued
evaluation after release to evaluate safety signs that may affect the benefit-risk ratio. These Phase IV
approval and
post-marketing surveillance studies. The focus of the
trials is on how drugs work in the real world. Anyone seeking treatment from their physician may be
treated with the therapy. Their personal physician monitors the results of treatment. Efficacy and
detection of rare or long-term adverse effects over a much larger patient population and longer time
period are evaluated, healthcare costs and outcomes are determined, and pharmacogenetics is studied.
New clinical indications for a drug may be established and large number of patients and physicians are
involved. The FDA may require that a developer conduct a Phase IV trial as a stipulation for drug
approval. Less than half of studies are completed or even initiated by developers. Phase IV trials may
result in a drug being removed from the market or restricted to certain indications.
Initially, these trials were run much like Phase III studies and were conducted for marketing purposes.
Studies were done at institutions with investigators familiar with clinical trials and had inclusion and
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exclusion criteria similar to those of Phase III studies. Results did not reflect what would happen under
normal conditions. As a result, innovative studies were designed to involve ordinary physicians in
naive research communities. Goals have been broadened and include evaluation of specific
pharmacological effects, establishing the incidence of adverse reactions, determining effects of long-
term administration of a therapy, establishing a new clinical indication for the therapy, evaluation of
the therapy in higher risk populations, etc. A main issue of concern is the mix of medical research and
clinical practice.
Phase V clinical trials refer to comparative effectiveness research and community-based research.
Research is done on data collected. All reported uses are evaluated. Patients are not monitored. Its main
focus is to determine integration of a new therapy into wide spread clinical practice. Filed under:
Cornell cooperative extension, evidence-based living, policy, the learning center tagged with:
cooperative extension programs, evaluation, evidence-based programs, research methods, research
translation.

Role of Institutional Ethics Committee (IEC) In Clinical Trials

Institutional Ethics Committee (IEC) is the committee formed of a group of people who go through the
research protocol / proposal and state whether or not it is ethically acceptable. Ethics are concerned
with the distinction between Right and Wrong, with moral choices, duties and obligations. The four
main principles of Biomedical Ethics are:
1. Autonomy: Autonomy (or respect for people) demands that the ability of competent subjects to
make their own decisions be recognized and respected, while also protecting the autonomy of the
vulnerable by preventing the imposition of unwanted decisions.
2. Non-maleficence: The principle dictating that harm should not come to individuals as a result of
their participation in a research project.
3. Beneficence: Beneficence is a concept in research ethics which states that researchers should have
the welfare of the research participant as a goal of any clinical trial or other research study.
4. Justice: Justice demands equitable selection of participants, i.e., avoiding participant populations
that may be unfairly coerced into participating, such as prisoners and institutionalized children.
All institutions which carry out any form of biomedical research involving human beings should
establish an appropriate IEC that is consistent with international and local guidelines and regulations.

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They must follow ICMR guidelines in India to protect safety and well-being of all participants and
should prevent unethical research.
Composition and responsibilities of IEC
Institutional Head constitutes an IEC and it is independent, competent and multidisciplinary unit. The
IEC appoints from among its members a chairperson who should be from outside the Institution and
not head of the same Institution, and the Member Secretary from the same Institution who conducts the
business of the committee. Members of IEC are:
1. Chairperson.
2. One to two persons from basic medical science.
3. One to two clinicians from various Institutes.
4. One legal expert or retired judge.
5. One social scientist/ representative of non-governmental voluntary agency.
6. One philosopher/ ethicist/ theologian.
7. One lay person from the community.
8. Member Secretary.
The Quorum (i.e. the minimum number of people required to conduct a meeting) has 5 persons
minimum. As per revised Schedule Y of Drugs & Cosmetics Act, 1940 which is amended in 2005, they
should be as:
1. One basic medical scientist (pharmacologist).
2. One clinician.
3. One legal expert or retired judge.
4. One social scientist/ representative of non-governmental organization/Philosopher/ ethicist/
theologian or a similar person.
5. One lay person from the community.
The members work to safeguard the interests and welfare of all sections of the community. If required,
subject experts could be invited to offer their views like a pediatrician for pediatric conditions, a
cardiologist for cardiac disorders etc. IEC has its own Standard Operating Procedures (SOPs) according
to which it functions. These SOPs are updated periodically and these ensure smooth functioning also.
An IEC must preferably be registered at the National Biomedical Research Authority as per the Bill
passed in 2007.

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 Responsibilities of IEC are to protect the dignity, rights and well-being of the potential research
participants, to ensure that universal ethical values and international scientific standards are expressed
and to assist in the development and the education of a research community responsive to local health
care requirements.
Functions of IEC
-secretary screens the research proposals for their completeness and depending on
the risk involved categorize them into 3 types:
1) Exemption from review for proposals that involve less than minimal risk.
2) Expedited review for more than minimal risk proposals, minor protocol amendments, research on
disaster management, and research on material collected during routine patient care like CT scans.
3) Full review for more than minimal risk and that involve vulnerable subjects.
The ethical review should be done in formal meetings by all primary reviewers and decision is made
only when quorum complete. The committee should meet at regular intervals and should not keep a
decision pending for more than 3 6 months. Periodic reviews are done as per the SOPs. All the
decisions are communicated in writing to the principal investigator (PI). Members should be
encouraged to attend trainings so that they are aware of all new guidelines and developments. Elements
of review are:

I. Scientific design, conduct of the study and approval of review committees.

II. Examination of predictable risks and potential benefits.
III. Procedure for selection of subjects including inclusion/ exclusion, withdrawal criteria and other
issues like advertisement details.
IV. Management of research related injuries, adverse events and compensation.
V. Justification for placebo and availability of products after the study.
VI. Patient information sheet and informed consent form in local language.
VII. Protection of privacy and confidentiality.
VIII. Plans for data analysis and reporting.
IX. Adherence to all regulatory requirements and applicable guidelines.
X. Competence of investigators, research and supporting staff, and facilities.
XI. Criteria for withdrawal of patients, suspending or terminating the study.
All documentation & communication of an IEC are dated, filed and preserved up to minimum of three
years after completion/termination of the study and strict confidentiality maintained during access and
retrieval procedures.
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 Informed Consent for Clinical Trials
The term informed consent is mistakenly viewed as the same as getting a research participant's
signature on the consent form. FDA believes that obtaining a research participant's verbal or written
informed consent is only part of the process. Informed consent involves providing a potential
participant with:
Adequate information to allow for an informed decision about participation in the clinical
investigation.
Facilitating the potential participant's understanding of the information.
An appropriate amount of time to ask questions and to discuss with family and friends the research
protocol and whether you should participate.
Obtaining the potential participant's voluntary agreement to participate.
Continuing to provide information as the clinical investigation progresses or as the subject or
situation requires.
What is Informed Consent?
As new medical products are being developed, no one knows for sure how well they will work, or what
risks they will find. Clinical trials are used to answer questions such as:
Are new medical products safe enough to outweigh the risks related to the underlying
condition?
How should the product be used? (for example, the best dose, frequency, or any special
precautions necessary to avoid problems),
How effective is the medical product at relieving symptoms, treating or curing a condition.
rtant for

While research subjects may get personal treatment benefit from

participating in a clinical trial, they must understand that they:
may not benefit from the clinical trial,
may be exposed to unknown risks,
are entering into a study that may be very different from the standard medical practices that they
currently know
To make an informed decision about whether to participate or not in a clinical trial, people need to be
informed about:
what will be done to them,

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 how the protocol (plan of research) works,
what risks or discomforts they may experience,
Participation being a voluntary decision on their part.
This information is provided to potential participants through the informed consent process. Informed
consent means that the purpose of the research is explained to them, including what their role would be
and how the trial will work. A central part of the informed consent process is the informed consent
document. The Food and Drug Administration (FDA) does not dictate the specific language required
for the informed consent document, but does require certain basic elements of consent be included.
Before enrolling in a clinical trial, the following information must be given to each potential
research subject:
A statement explaining that the study involves research.
An explanation of the purposes of the research.
The expected length of time for participation.
A description of all the procedures that will be completed during enrollment on the clinical trial.
Information about all experimental procedures the will be completed during the clinical trial.
A description of any predictable risks.
Any possible discomforts (e.g., injections, frequency of blood test etc.) that could occur as a result
of the research.
Any possible benefits that may be expected from the research.
Information about any alternative procedures or treatment (if any) that might benefit the research
subject.
A statement describing:
o the confidentiality of information collected during the clinical trial,
o how records that identify the subject will be kept
o The possibility that the FDA may inspect the records.
For research involving more than minimal risk information including
an explanation as to whether any compensation or medical treatments are available if injury occurs,
what they consist of, or
Where more information may be found.
questions about the research,
research subjects' rights,
Injury related to the clinical trial.

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 Research subject participation is voluntary,
Research subjects have the right to refuse treatment and will not losing any benefits for which they
are entitled,
Research subjects may choose to stop participation in the clinical trial at any time without losing
benefits for which they are entitled.

INFORMED CONSENT: PROCESS AND DOCUMENTATION

Every investigator and clinical research coordinator (CRC) should recognize the importance of
obtaining valid and appropriate informed consent as an important protection of the rights and welfare
of human subjects. Indeed, the very first principle of the Nuremberg Code1, which represents the
gen
Obtainment of informed consent involves both the process which is the consent dialogue and the
documentation of obtaining informed consent on the IRB-EC approved informed consent form (ICF).
Unfortunately, the current HHS and FDA regulations which set the requirements for informed consent

only under circumstances that provide the prospective subject or the representative
sufficient opportunity to consider whether or not to participate and that minimize the possibility of
coercion or undue influence.
The lack of detail regarding the process of informed consent in both the regulations and in FDA/OHRP
guidance is not surprising since these regulations were promulgated in 1981 and the informed consent
requirements have never been revised or updated. On the other hand, there has been a remarkable
evolution of medicine with its sophisticated healthcare technologies. Concomitantly, the field of
research ethics has also evolved including emphasis on informed consent ethics as evidenced by a very
extensive literature on this topic. Indeed, there have been many national and international working
groups, as well as numerous ACRP conference sessions, devoted to identifying ways to improve
informed consent including more attention paid to the consent process. Given the current length and
complexity of ICFs, the need for research personnel to engage prospective subjects in an effective
informed consent process has become critical.
One of the most advanced international guidelines on the informed consent process was put forth by the
Council for Internationa

contact is made with a prospective subject and continues throughout the course of the study. By
informing the prospective subjects, by repetition and explanation, by answering their questions as they
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arise, and by ensuring that each individual understands each procedure, investigators elicit their
informed consent and in doing so manifest respect for their dignity and autonomy. Each individual
must be given as much time as is needed to reach a decision, including time for consultation with
family
must not be simply a ritual recitation of the contents of a written document. Rather, the investigator

investigator must then ensure that the prospective subject has adequa
The following are the characteristics of the process as it is carried out from the location of the initial

process. Since informed consent is necessarily an on-

participation in the research, this extension of the process will also be addressed.

Environment
The environment where the process of consent is conducted should be determined by the type of

setting is afforded to facilitate a constructive dialogue between the prospective subject and the
person(s) involved in obtaini
an appropriate location whereas a patient waiting room or a pre-op area would be examples of locations
which may not be conducive to the obtainment of legally effective informed consent. Patients in these
latter environments may exhibit stress associated with illness or procedural related anxieties (e.g., fear
of pending surgery, cardiac catheterization, chemotherapy) which could compromise the process of
consent.
Assessment of Capacity to Consent
All prospective subjects must have the cognitive ability to provide legally effective informed consent.
Individuals who do not have such ability (i.e., decisionally impaired persons) can only be enrolled in
research through consent of their legally authorized representative (LAR). If there is any concern about

individual. Different clinical specialties have specific standards for assessing cognitive capacity in very
diverse patient groups.

Presentation of the Elements of Informed Consent

The required elements of informed consent should be presented and discussed with the prospective
subject in a sequential manner utilizing the approved ICF as a guide. The presentation should be
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structured to facilitate a dialogue with reinforcement and elaboration of important information (e.g., the

evaluate whether the process is achieving the goal which is obtainment of legally effective informed
consent from the subject. In addition to paying attention to general signs of information receptivity, it is
often helpful to ask open-ended questions in order to identify points of confusion which require
clarification.
Use of a Delayed Consent Procedure
The amount of time allotted to the process of consent is dependent upon the nature and complexity of
the research and the need to minimize the possibility of coercion or undue influence. In some research
(e.g., complex or risky research) a delayed consent procedure should be used in order to afford the
subject the opportunity to discuss participation in the research with family, friends, counselors, or other
confidants before they sign the ICF. If the individual is uncomfortable or anxious about participating in
the research they should be instructed to take the ICF home for further review and consideration before
deciding whether or not to participate in the research.
Assessm
Investigators and other research personnel involved in obtaining informed consent have a legal and an
ethical obligation to ensure that the prospective subject has sufficient knowledge and comprehension of
all the elements of informed consent to enable him/her to make an informed and enlightened decision
whether or not to participate in the research. The fact that an individual is prepared to sign the ICF and
has no unanswered questions does not necessarily represent sufficient evidence of an adequate level of
comprehension. Some investigators and CRCs, therefore, choose to determine the level of
comprehension by questioning the individual concerning their understanding of the elements of
informed consent. Alternatively, the prospective subject can be asked to explain in his/her own words
their understanding of the research. In some cases computer technology is used to assess
comprehension through the use of multiple choice tests. This method, however, is not commonly
utilized.
Documentation of Informed Consent
Documentation of informed consent is the conclusion of the initial consent process. Whoever
documents the obtainment of informed consent (i.e., signs the ICF) must be qualified to attest to the
fact that the subject has provided legally effective informed consent. While a number of qualified
research personnel can, and should, be involved in the process of consent, it should be remembered that
the Principal Investigator (PI) is ultimately responsible for all aspects of the research including
informed consent. Therefore, it is incumbent upon the PI to be involved in both the process and
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documentation of informed consent, particularly in studies involving investigational drugs or devices
under an IDE. However, if the PI is unavailable, a sub-investigator with appropriate expertise who is
-
approved drugs or procedures involving minimal risk, it may be acceptable to have non-physicians (e.g.
CCRCs) to both conduct the process and document the obtainment of informed consent. The individual
who assumes responsibility for documentation of informed consent and the consenting subject should
sign and date the ICF, preferably in e

out of an abundance of caution, require both the date and the time that the signatures were obtained.
Finally it has become common practice for the ICF signature blanks to have an associated certification
statement which represents the consent attestation.
Ongoing Consent
Compliance with regulations as well as ethical conduct of research requires that subjects be informed
of new findings that may influence their continued participation in te research. In certain instances it is
appropriate to actively seek continued permiss
interests may change over time, even in the absence of material changes in the research protocol.
Indeed, some subjects forget they are participating in research which, in turn, perpetuates therapeutic
misconception. Therefore, while regulations do not require re-consent, good ethics may. Depending
upon the nature of the research and the subject population, the PI should ensure that written
documentation of the re-consent is obtained at various intervals.

Health Insurance Portability and Accountability Act (HIPAA)

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) required the Secretary of
the U.S. Department of Health and Human Services (HHS) to develop regulations protecting the
privacy and security of certain health information. To fulfill this requirement, HHS published what are
commonly known as the HIPAA Privacy Rule and the HIPAA Security Rule. The Privacy Rule, or
Standards for Privacy of Individually Identifiable Health Information, establishes national standards for
the protection of certain health information. The Security Standards for the Protection of Electronic
Protected Health Information (the Security Rule) establish a national set of security standards for
protecting certain health information that is held or transferred in electronic form. The Security Rule
operationalizes the protections contained in the Privacy Rule by addressing the technical and non-

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 -PHI). Within HHS, the Office for Civil Rights
(OCR) has responsibility for enforcing the Privacy and Security Rules with voluntary compliance
activities and civil money penalties.

allowing covered entities to adopt new technologies to improve the quality and efficiency of patient
care. Given that the health care marketplace is diverse, the Security Rule is designed to be flexible and
scalable so a covered entity can implement policies, procedures, and technologies that are appropriate
-PHI.
Statutory and Regulatory Background of HIPAA: The Administrative Simplification provisions of
the Health Insurance Portability and Accountability Act of 1996 (HIPAA, Title II) required the
Secretary of HHS to publish national standards for the security of electronic protected health
information (e-PHI), electronic exchange, and the privacy and security of health information. HIPAA
called on the Secretary to issue security regulations regarding measures for protecting the integrity,
confidentiality, and availability of e-PHI that is held or transmitted by covered entities. HHS developed
a proposed rule and released it for public comment on August 12, 1998. The Department received
approximately 2,350 public comments. The final regulation, the Security Rule, was published February
20, 2003.2 The Rule specifies a series of administrative, technical, and physical security procedures for
covered entities to use to assure the confidentiality, integrity, and availability of e-PHI.
Who is covered by the Security Rule?
The Security Rule applies to health plans, health care clearinghouses, and to any health care provider
who transmits health information in electronic form in connection with a transaction for which the
Secretary of HHS has adopted standards under HIPAA
associates.

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 PHARMACOVIGILANCE
Pharmacovigilance is defined as the science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other drug-related problem. World Health
Organization (WHO) established its Programme for International Drug Monitoring in response to the
thalidomide disaster detected in 1961. The aims of Pharmacovigilance are
a) To enhance patient care and patient safety in relation to the use of medicines;
b) To support public health programmes by providing reliable, balanced information for the
effective assessment of the risk-benefit profile of medicines.
Pharmacovigilance plays a key role in the healthcare system through assessment, monitoring and
discovery of interactions amongst drugs and their effects in human. Pharmaceutical and
biotechnological medicines are designed to cure, prevent or treat diseases; however, there are also risks
particularly adverse drug reactions (ADRs) can cause serious harm to patients. Thus, for safety
medication ADRs monitoring required for each medicine throughout its life cycle, during development
of drug such as pre-marketing including early stages of drug design, clinical trials, and post-marketing
surveillance.
Pharmacovigilance setup
When adverse effects and toxicity appear, particularly when previously unknown in association with
the medicine, it is essential that they are analyzed and communicated effectively to an audience that has
the knowledge to interpret the information. This is the role of PV, of which much has already been
achieved. But more is required for the integration of the discipline into clinical practice and public
policy. To fulfill the PV obligations for its marketed products as per regulations, a pharmaceutical
company has to essentially carry out activities such as collection, and expedited reporting of serious
unexpected ADRs. A typical setup for PV studies, including people involved on various levels,
organizational units and their functions are shown in Figure 1.

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 Figure 1: A typical Pharmacovigilance setup

Role of Pharmacovigilance in Clinical Trials

Clinical trials are used throughout the world to determine the safety and efficacy of a chemical or
biological compound with respect to its actions on symptoms or a known disease process. There are
r animal studies have been completed:
I. Phase 1 clinical trials represent the first use in humans, with studies involving healthy volunteer
humans as opposed to animal models. The aim is to begin to establish the safety profile of the
drug in question, determining the potential for both beneficial and adverse effects. The studies
examine the pathways through which the drug is absorbed, distributed in the body, metabolized
and eliminated and the maximum tolerable dose. They can also study proposed formulas and
dosage (frequency and scheduling) for further trials. The primary focus is on safety rather than
efficacy, with studies usually lasting only a few days or a few weeks. Phase I studies might
typically require 12 months to complete and involve comparatively few subjects (<100).

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 Serious Adverse Events (SAEs) are relatively rare and every effort is made to minimize any risk
to the participants. For some drugs known to be toxic (such as those used in the treatment of
cancer) Phase I studies in healthy volunteers may not be possible for ethical reasons..
II. Phase II trials aim to study the drug as administered to patients who already have the disease
which the drug may have the potential to treat. The objective is to determine the optimal dose
and dosing regimen, one which delivers maximal efficiency alongside acceptable adverse
effects. Phase II trials may also investigate metabolism and excretion in more depth and
establish safety and efficacy markers for subsequent trials. The scale is larger, running up to
hundreds of patients (200-300), lasting several weeks or months and often uses a double blind
design where a standard of care comparator product or placebo is used to benchmark the

III. Phase III trials usually involve hundreds or even thousands of patients and may require several
years for completion. The ultimate aim is to gain statistically significant scientific proof of a
positive benefit-risk profile of the medicinal product which is required for regulatory approval
and often the favored design is again double blind with randomized allocation of patients to
receive active drug or placebo or active comparator treatment. It will depend on the drug and
disease as to whether the current standard therapy is used as a comparator for the results, or
whether they are compared to a placebo. If a serious disease for which there is already an
effective treatment is being studied, the new drug may be given in addition to the established
treatment, to determine if it can increase the effectiveness, compared to patients receiving
placebo in addition to the established therapy. There is no guarantee that any trial in this phase
will result in a Marketing Authorization (MA) and naturally the oversight of an effective pre-
and post-marketing Pharmacovigilance system is a critical component of any application for
an MA. After successful completion of Phase III clinical trials and authorization for marketing,
the pharmaceutical company may conduct phase IV trials in order to continue to monitor the
drug on a much larger scale and in a less controlled real world environment.
IV. Different types of studies can be included in phase IV clinical trials, which is conducted
following the granting of a Marketing Authorization (MA). The drug has often been placed onto
the market (although there are cases this does not always happen directly after authorization).
However, regulators do often require some typ -

This may be to clarify issues which were not resolved during Phase III but that regulators did
not classify as a cause to delay marketing. Size and designs can vary, sometimes consisting of
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 classical clinical trials, sometimes epidemiological studies studying large populations using
databases or registries of treated patients.

Clinical trial safety is an important component of Pharmacovigilance. Every medicinal product must
have satisfactorily completed a clinical trial programme establishing acceptable evidence of safety and
efficacy before being placed onto the market. Clinical Trials are closely monitored by an investigator
and the pharmaceutical company involved in the research and development of a medicinal product.
But, the process also benefits from autonomous review by Independent Review Boards, Ethics
Committees and drug safety firms. This is where Pharmacovigilance fits into this process; to provide
an extra level of security to ensure that safe and effective products reach patients. As part of the global
healthcare and pharmaceutical system, manufacturers, drug developers, and investigators all have the
responsibility to provide the best possible care for the patients and consumers around the world.
An investigator shall report any serious adverse event which occurs in a subject at a trial site at which
he is responsible for the conduct of a clinical trial immediately to the sponsor. Following the immediate
report of a serious adverse event, the investigator shall make a detailed written report on the event. The
sponsor shall keep detailed records of all adverse events relating to a clinical trial which are reported to
him by the investigators for that trial.
A sponsor shall ensure that all relevant information about a suspected unexpected serious adverse
reaction which occurs during the course of a clinical trial and is fatal or life-threatening is recorded and
reported as soon as possible to the federal drug authority.
The federal authority shall keep a record of all suspected unexpected serious adverse reactions relating
to an investigational medicinal product which are brought to its attention.

Pharmacovigilance in Herbal and Traditional Medicines

The use of herbal and traditional medicines raises concerns in relation to their safety. There is wide

based on tradition, assures both its efficacy and safety. There are examples of traditional and herbal
medicines being adulterated or contaminated with allopathic medicines, chemicals such as
corticosteroids, non-steroidal anti-inflammatory agents and heavy metals. Many traditional medicines
are manufactured for global use and they have moved beyond the traditional and cultural framework
for which they were originally intended. Self-medication further aggravates the risk to patients. When
traditional and herbal medicines are used in conjunction with other medicines there is the potential of
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serious adverse drug interactions. For all these reasons, inclusion of herbal and traditional medicines in
national Pharmacovigilance programmes has become important and inevitable. Healthcare providers,
including traditional health practitioners, regulators, manufacturers and the public share a responsibility
for their informed and safe use. The World Health Organization has produced guidelines for
assessment of the safety, efficacy and quality of herbal medicines
Pharmacovigilance in Vaccines and biological medicines
For several reasons, vaccines and biological require modified systems of safety monitoring. They are
often administered to healthy children. This applies particularly to vaccines used within a national
immunization programme. In many countries, those exposed to a particular vaccine represent the entire

high, and they are reluctant to countenance even a small risk of adverse events. Concerns regarding
vaccine safety, real or imagined, may result in loss of confidence in entire vaccine programmes. This
can result in poor compliance and a consequent resurgence in morbidity and mortality of vaccine-
preventable disease. It is essential that there should be adequate safety surveillance supporting
immunization programmes. The skills and infrastructure to deal with genuine adverse events are
essential in preventing or managing misplaced fear caused by false or unproven signals from patients
and health workers that might adversely affect immunization cover. For example, concerns about the
safety of whole-cell Pertussis resulted in dramatic reductions in vaccines coverage and a resurgence of
Pertussis in many countries.
New vaccines for pandemic diseases such as HIV/AIDS and malaria are in the later phases of
development. Clinical trials in large patient populations are being considered for testing the efficacy
and safety of these vaccines. Special ethical, legal and regulatory challenges are raised in the conduct
of such clinical trials, especially the implications vaccines may have for the epidemiology of disease
and the possible direct and indirect risks of harm associated with the introduction of vaccines into large
communities.
In recent years, the safety of biological products and blood products has come under public scrutiny.
Concerns about the safety of medicinal products of animal origin have been raised in connection with
variant Creutzfeldt-Jacob disease (vCJD), and with contamination of blood and blood products by
infectious organisms such as HIV and hepatitis B. The quality of screening and sterilization procedures
and appropriate selection of donors are linked to the risks of contamination. Such safety issues related
to the use of plasma-derived medicinal products should fall under the aegis of Pharmacovigilance
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programmes. For that to happen, Pharmacovigilance centers would have to consider the special issues
related to safety of these products. Expertise in biological products, virology and medical microbiology
would be required.
Other products likely to be regulated by the drug regulatory authority include veterinary medicines,
biotechnology products, and genetically derived or genetically modified medicinal products. These
products are all likely to pose unusual challenges in safety monitoring. They will require special and
possibly various types of expertise to assess safety concerns arising from their use. Such expertise may
not be available within the regulatory authority. Collaboration and consultation with appropriate
experts within the country or in other countries may be necessary.

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