GENERIC DRUG APPROVAL

What are generic drugs?

A generic drug is a medication created to be the same as an already marketed brand-name drug in
dosage form, safety, strength, route of administration, quality, performance characteristics, and
intended use. These similarities help to demonstrate bioequivalence, which means that a generic
medicine works in the same way and provides the same clinical benefit as its brand-name
version. In other words, you can take a generic medicine as an equal substitute for its brand-name
counterpart.
Why do brand-name drugs look different from their generic versions?
Trademark laws in the United States do not allow a generic drug or medicine to look exactly like
other drugs already on the market. Generic medicines and brand-name medicines share the same
active ingredient, but other characteristics, such as colors and flavorings, that do not affect the
performance, safety, or effectiveness of the generic medicine, may be different.
Why do generic medicines cost less than brand-name medicines?
Generic drugs or medicines become available only after a rigorous review by FDA and after a set
period of time that the brand-name version has been on the market exclusively. This is because
new drugs, like other new products, are usually protected by patents that prohibit others from
making and selling copies of the same drug. The patent protects the company's investment in the
drug's development by giving the company the sole right to sell the drug while the patent is in
effect. Because it takes such a long time to bring a new drug to market, this period of exclusivity
allows drug companies to recoup the costs associated with bringing a new drug to market. 
Once these patents and marketing exclusivities expire (or if the patents are successfully challenged
by the generic drug company), the generic drug can be approved.
Generic drugs also tend to cost less than their brand-name counterparts because generic drug
applicants do not have to repeat animal and clinical (human) studies that were required of the
brand-name medicines to demonstrate safety and effectiveness. This is why the application is
called an “abbreviated new drug application.” This, together with competition between the brand-
name drug and multiple generic drugs, is a large part of the reason generic medicines cost much
less.
What Is the Approval Process for Generic Drugs?

 Generic drugs are copies that one company makes of a brand-name drug that was
developed by another company.  Generally, generic drugs sell at lower prices, and it is in
the public's interest to get generic drugs to the market quickly. 
 But, like any other scientific and regulatory process, approval of a generic drug takes time. 
It takes FDA time to review the complex information needed to demonstrate that a given
generic drug can be substituted for the brand-name drug that it copies, and that time also
depends on the complexity of the drug product and the completeness of the application. 
 Here is why:
Prescription drugs have significant, sometimes life-saving, positive effects, but they also may
present significant risks.  FDA approves a drug only after review of extensive testing showing that
a drug will provide the benefits described in its labelling, and that those outweigh its risks. 
As a copy of the brand-name drug FDA originally reviewed, a generic drug application submitted
to FDA for approval must show that: points are listed below

What standards must generic medicines meet to receive FDA approval?

Drug companies can submit an abbreviated new drug application (ANDA) for approval to market
a generic drug that is the same as (or bioequivalent to) the brand-name version. FDA's Office of
Generic Drugs reviews the application to make certain drug companies have demonstrated that
the generic medicine can be substituted for the brand-name medicine that it copies.
An ANDA must show the generic medicine is equivalent to the brand in the following ways:

 The active ingredient is the same as that of the brand-name drug/innovator drug.
o An active ingredient in a medicine is the component that makes it pharmaceutically
active — effective against the illness or condition it is treating.
o Generic drug companies must provide evidence that shows that their active
ingredient is the same as that of the brand-name medicine they copy, and FDA must
review that evidence.

 The generic medicine is the same strength.

 The medicine is the same type of product (such as a tablet or an injectable).

 The medicine has the same route of administration (such as oral or topical).

 It has the same use indications.

 The inactive ingredients of the medicine are acceptable.

o Some differences, which must be shown to have no effect on how the medicine
functions, are allowed between the generic and the brand-name version.
o Generic drug companies must submit evidence that all the ingredients used in their
products are acceptable, and FDA must review that evidence.

 It lasts for at least the same amount of time.

o Most medicines break down, or deteriorate, over time.
o Generic drug companies must do months-long "stability tests" to show that their
versions last for at least the same amount of time as the brand-name.

 It is manufactured under the same strict standards as the brand-name medicine.

o It meets the same batch requirements for identity, strength, purity, and quality.
o The manufacturer is capable of making the medicine correctly and consistently.
 Generic drug manufacturers must explain how they intend to manufacture
the medicine and must provide evidence that each step of the manufacturing
process will produce the same result each time. FDA scientists review those
procedures, and FDA inspectors go to the generic drug manufacturer's facility
to verify that the manufacturer is capable of making the medicine consistently
and to check that the information the manufacturer has submitted to FDA is
accurate.
 Often, different companies are involved (such as one company manufacturing
the active ingredient and another company manufacturing the finished
medicine). Generic drug manufacturers must produce batches of the
medicines they want to market and provide information about the
manufacturing of those batches for FDA to review.

 The container in which the medicine will be shipped and sold is appropriate.

 The label is the same as the brand-name medicine's label.

 o The drug information label for the generic medicine should be the same as the
brand-name label. One exception is if the brand-name drug is approved for more
than one use and that use is protected by patents or exclusivities. A generic medicine
can omit the protected use from its labelling and only be approved for a use that is
not protected by patents or exclusivities, so long as that removal does not take away
information needed for safe use. Labels for generic medicines can also contain certain
changes when the drug is manufactured by a different company, such as a different
lot number or company name.

 Relevant patents or exclusivities are addressed.

o As an incentive to develop new medicines, drug companies are awarded patents and
exclusivities that may delay FDA approval of applications for generic medicines.
FDA must comply with the delays in approval that the patents and exclusivities
impose.
The ANDA process does not, however, require the drug applicant to repeat costly animal and
clinical research on ingredients or dosage forms already approved for safety and effectiveness.
This allows generic medicines to be brought to market more quickly and at lower cost, allowing
for increased access to medications by the public.
APPROVAL AND MARKETING OF OTC HUMAN DRUGS

1.  What is an Over-the-Counter (OTC) Drug Product?

An OTC drug product is a drug product marketed for use by the consumer without the
intervention of a health care professional in order to obtain the product. Two post-1938 regulatory
pathways exist for the legal marketing of such products:

 marketing in compliance with an OTC drug monograph

  marketing under the authority of an approved product-specific new drug application
(NDA), or an abbreviated new drug application (ANDA)

2.  What is a prescription drug product?

A prescription drug product is a drug product approved for marketing that can only be obtained
with a prescription from an appropriate health care practitioner.

3.  What is the OTC drug review?

The OTC drug review was established to evaluate the safety and effectiveness of OTC drug
products marketed in the United States before May 11, 1972. It is a three-phase public rulemaking
process (each phase requiring a Federal Register publication) resulting in the establishment of
standards (monographs or non-monographs) for an OTC therapeutic drug category.

4.  What is the first phase of the OTC drug review?

The first phase was accomplished by advisory review panels. The panels were charged with
reviewing the ingredients in non-prescription drug products to determine whether these
ingredients could be generally recognized as safe and effective for use in self-treatment. They were
also charged with reviewing claims and recommending appropriate labelling, including
therapeutic indications, dosage instructions, and warnings about side effects and preventing
misuse.

According to the terms of the review, the panels classified ingredients in three categories as
follows:

 Category I: generally recognized as safe and effective for the claimed therapeutic indication;

 Category II: not generally recognized as safe and effective or unacceptable indications;

 Category III: insufficient data available to permit final classification

5. What is the second phase of the OTC drug review?

The second phase of the OTC drug review was the agency’s review of ingredients in each class of
drugs, based on the panel’s findings, on public comment, and on new data that may have become
available. The agency, in turn, publishes its conclusions in the Federal Register in the form of a
tentative final monograph. After publication of the tentative final monograph, a period of time is
allotted for objections to the agency’s proposal or for requests to be submitted for a hearing before
the Commissioner of FDA.

6.  What is the third phase of the OTC drug review?

The publication of final regulations in the form of drug monographs is the third and last phase of
the review process. The monographs establish conditions under which certain OTC drug products
are generally recognized as safe and effective.

Drug Product Applications

7.  What is a human drug application?

The term human drug application means an application for:

 approval of a new drug submitted under section 505(b)(1) of the Federal Food, Drug, and
Cosmetic Act (FD&C Act)
  approval of a new drug submitted under section 505(b)(2) of the FD&C Act

 approval of an abbreviated new drug application under section 505(j) of the FD&C Act

 licensure of certain biological products under section 351 of the Public Health Service Act

10. What is an Abbreviated New Drug Application (505) (j)?

An abbreviated new drug application is described under section 505(j) of the Act as an application
that contains information to show that the proposed product is identical in active ingredient,
dosage form, strength, route of administration, labelling, quality, performance characteristics and
intended use, among other things to a previously approved application (the reference listed drug
(RLD)). ANDAs do not contain clinical studies as required in NDAs but are required to contain
information establishing bioequivalence to the RLD. In general, the bioequivalence determination
allows the ANDA to rely on the agency’s finding of safety and efficacy for the RLD.

10. What is an Abbreviated New Drug Application (505) (j)?

An abbreviated new drug application is described under section 505(j) of the Act as an application
that contains information to show that the proposed product is identical in active ingredient,
dosage form, strength, route of administration, labelling, quality, performance characteristics and
intended use, among other things to a previously approved application (the reference listed drug
(RLD)). ANDAs do not contain clinical studies as required in NDAs but are required to contain
information establishing bioequivalence to the RLD. In general, the bioequivalence determination
allows the ANDA to rely on the agency’s finding of safety and efficacy for the RLD.

 Prescription to OTC Switch

16.  What is prescription to OTC switch?

Prescription to OTC switch refers to over-the-counter marketing of a product that was once a
prescription drug product, for the same dosage form, population, and route of administration.

17. How is a prescription to OTC switch accomplished?

An efficacy supplement should be submitted to an approved NDA for a prescription product if the
sponsor plans to switch the drug product covered under the NDA to OTC marketing status in its
entirety without a change in the previously approved dosage form or route of administration. An
NDA 505(b)(1) should be submitted if the sponsor is proposing to convert some but not all of the
approved prescription indications to OTC marketing status. An original NDA (505)(b)(1) or 505(b)
(2) needs to be submitted if the sponsor plans to market either a new product OTC whose active
substance, indication, or dosage form has never previously been marketed OTC.

Drug Applications for Over-the-Counter (OTC)

Drugs
FDA's review of OTC drugs is primarily handled by CDER's Office of Non-prescription Drugs.
The Non-prescription Drug Advisory Committee meets regularly to assist the agency in
evaluating issues surrounding these products. This committee has played a major role in the
growth of prescription to OTC switches in recent years.

Because there are over 300,000 marketed OTC drug products, FDA reviews the active ingredients
and the labelling of over 80 therapeutic classes of drugs, for example analgesics or antacids,
instead of individual drug products. For each category, an OTC drug monograph is
developed and published in the Federal Register. OTC drug monographs are a kind of "recipe book"
covering acceptable ingredients, doses, formulations, and labelling. Many of these monographs
are found in section 300 of the  Code of Federal Regulations.

Once a final monograph is implemented, companies can make and market an OTC product
without the need for FDA pre-approval. These monographs define the safety, effectiveness, and
labelling of all marketing OTC active ingredients.

New products that conform to a final monograph may be marketed without further FDA review.
Those that do not conform must be reviewed by the New Drug Application process. A drug
company may also petition to change a final monograph to include additional ingredients or to
modify labelling. 

FDA’s APPROVAL PROCESS OF OTC PRODUCTS

The Food, Drug, and Cosmetic Act of 1938 was the first piece of legislation to require that drugs be
cleared by the U.S. Food and Drug Administration before being marketing for human use. This
act required that all new drugs be proved safe for human use before marketing, prohibited the
sale of dangerous, contaminated or misbranded products, and mandated labeling specifications.

A new drug application (NDA) has been required for all new drug entities that have been
introduced since the enactment of the Food, Drug, and Cosmetic Act. After an NDA is approved
by the FDA, the drug product may be marketed only by the sponsor of the NDA. Additional
manufacturers who wish to market similar products must seek approval to do so through
submission of a separate NDA. In some cases, such as with generic medications, an abbreviated
NDA may be submitted. NDAs are updated periodically to include post marketing information
and minor label changes. Labeled with sufficient instructions to allow safe, unsupervised use by
consumers, these amendments allowed labeling directed to physicians and pharmacists instead of
to consumers. Drugs with physician- and pharmacist-directed labeling were then available by
prescription only.

In 1962, the Kefauver-Harris amendments to the Food, Drug, and Cosmetic Act were passed,
requiring that drug products be proved not only safe but also effective for their intended uses.

Enactment of these amendments compelled the FDA to determine the effectiveness of more than
4,000 newer drug products, including more than 500 OTC products that had been marketed before
the enactment of the amendments. The OTC Drug Review was begun in 1972 as an FDA-initiated
scientific review of OTC product ingredients in use at that time to ensure that appropriate safety,
effectiveness and labelling standards are met. This review process consists of three phases: an
advisory panel review, creation of a tentative monograph and publication of a final monograph

As a result of the initial OTC drug review findings, If OTC ingredients determined to be safe and
effective for their intended uses subsequently the FDA approved these products for general use.
And if found to be ineffective, these are considered to be unsafe. And the some cases required
submission of additional data before safety and effectiveness could be established by FDA

OTC REGUALTORY PATHWAYS

Two post-1938 regulatory pathways exist for the legal marketing of such products:

 Marketing in compliance with an OTC drug monograph

 marketing under the authority of an approved product-specific new drug

application (NDA), or an abbreviated new drug application (ANDA)

Two regulatory pathways exist for the legal marketing of such products:

NDA process.
OTC Monographs’
There are seven principles which FDA needs to consider before switching. They can be listed as

1) Ease/possibility of self-diagnosis
2) Self-limited or chronic condition

3) Benefit/risk ratio and its evaluation

4) Low potential in harm

5) Number of adverse drug reactions or interactions and ease of detecting them

6) Long term data from prescription use

7) Toxicity compared with other drugs in the class.

The Switch Process:

The process of reclassifying drugs from prescription to OTC status is referred to as an "Rx to OTC
switch." FDA regulations identify processes for initiating consideration of an Rx to OTC switch. A
proposal under this regulation to exempt a drug from prescription-only requirements may be
initiated by the Commissioner or by "any interested person" in the form of a sponsor submitting a
supplement to an approved new drug application (NDA) or, as in your case, by a third party
petitioning FDA. Regardless of who initiates a request for an OTC switch, however, the evidence
must demonstrate that the prescription-only dispensing requirements are no longer necessary to
protect the public health due to drug's toxicity or other potentiality for harmful effect, or by reason
of the method of the drug's use. Evidence must also demonstrate that the drug is safe and effective
for use in self-medication as directed in proposed labelling

Drugs are commonly switched one of two ways: under the "OTC drug review," or by a
manufacturer's submission of additional information to the original new drug application.
INDIA:

In India OTC has no legal recognition, drugs which are not included in the list of prescription-only
drugs are considered to be non-prescription drugs (or OTC drugs). Hence, OTC drugs means
drugs legally allowed to be sold Over the Counter by pharmacists, i.e. without the prescription of
a Registered Medical Practitioner or a physician. Prescription-only drugs are those medicines that
are listed in Schedules H and X of the Drug and Cosmetics Act 1940 and Drugs and Cosmetics
Rules. OTC drugs registered as “Ayurvedic Medicine” (i.e. traditional Indian system of medicines
containing natural / herbal ingredients) are also regulated by the DCA (Drugs and Cosmetics Act)
and DCR (Drugs and Cosmetics Rules).

India currently ranks 11th in the global OTC size. It is estimated that it will reach 9th position
within five years. The Indian OTC market was estimated at approximately USD 1,813 million
(euro 1362 million) with an annual growth rate of 10.7% at the end of calendar year 2009.

SWITCH TREND IN INDIA:

There are many products in the Rx sector which could be revitalised through OTC switches in
India. An analytical interpretation of various data places the focus on vitamins, cough & cold,
antacids, antipyretics and NSAIDs as opportunity areas for switch in India. India does not have a
well-documented process or a specific regulation on switching Rx to OTC products and this is the
need of the hour. Globally many countries have a formal process of transferring prescription (Rx)
drugs to over-the-counter (OTC) status, known as "Rx-to-OTC switch. In these markets Rx to OTC
switch is also seen as an efficient way of reducing healthcare costs by expanding the most
inexpensive form of health care with OTC medicines. Regulators in India should clearly define
OTC formally as a category because this would help promote access to market and will empower
consumers who want to take a more active role in their own health care. In fact, in the near future,
switching would be one of the most used strategies to enter OTC by new players.

MARKETING AUTHORIZATION

The major source for pharmaceutical regulation is the Drugs and Cosmetics Act (DCA) and its
subordinate legislation, the Drugs and Cosmetics Rules (DCR). This legislation applies to the
whole of India and to all sorts of medicines (e.g. allopathic, ayurvedic, homeopathic, etc.) whether
imported or made in India. The legislation is enforced by the Central Government (Ministry of
Health & Family Affairs) in New Delhi, which is responsible for its overall supervision. The office
of the Drugs Controller General of India (DCGI) has prime responsibility for approving all new
molecules and unique new formulations. However, power to provide manufacturing and selling
licenses which are the two main registrations required to manufacture and sell a drug – belongs to
each individual State government through its Food and Drug Administration (FDA), who also
carry out enforcement of DCA and DCR. Matters of new molecule approval and standards, clinical
trials, introduction of a new unique formulation and import licenses are handled by the DCGI.

INDIAN O.T.C. PHARMACEUTICALS MARKET

Indian market faces the problem of ‘Deemed OTC market’ where in ethical drugs are also sold
without a prescription due to poor monitoring and control by FDA. Self-medication tendency is
traditionally very high due to the high availability of traditional medicines, the awareness and
acceptance of which is very high among the public. The Indian OTC pharmaceuticals market
generated total revenues of $2.5 billion in 2006,this representing a compound annual growth rate
of 8.3%for the five year period spanning 2002- 2006.In comparison ,the US and Chinese OTC
pharmaceuticals markets grew with CAGRs of 4.3% and 7% over the same period ,to reach
respective values of $21.2billion and $11.9billion in 2006. Traditional medicines proved the most
lucrative for the Indian OTC pharmaceuticals market in 2006, generating total revenues of $679.3
million. In comparison, sales of cough and cold preparations generated revenues of $492.6 million
in 2006