Rohit thanage Roll no 24 28/5/2010

tanktherapistBiotechnology

Oct 23, 2013 (3 years and 9 months ago)

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Overview of regulatory applications for
generic drugs

Rohit

thanage

Roll no 24

28/5/2010

3 largest markets

ThrEE

of
ThE

world’S

largEST

pharmacEUTical

markETS

are the United States
(U.S.), the European

Union (EU), and Japan.


Drug

manufacturers

spend

a

tremendous

amount

of

time,

money

and

effort

ensuring

that

drug

approval

applications

meet

the

necessary

regulatory

requirements

for

approval


Nonetheless
, the application process continues post approval with the ongoing

reporting requirements necessary for implementing changes to an approved
application.


The
U.S. and

the EU have made efforts to reduce regulatory reporting burdens. On the other
hand, Japan tends

to require more detail for reporting changes and has excessive review times for
approval of certain

modifications

National procedure

Uk

MHRA

Get MAA grant

italy

RMS

CMS

Dossier report is send

Feels satisfactory

Grant approval

Mutual recognition procedure

Start manufacturing as per guidelines

Decentralized procedure

A combination of MRP and national procedure

rms

cms

cms

cms

cms

8000 pounds

10000 pounds

Simultaneous dossier submission to all countries

210 days

Query

Rms

reviews

Query ???


If there is a
dispute between
Member States,
the points under
dispute can be
referred to the
EMEA for
arbitration.

Centralized procedure

Community
authorization
procedure

compulsory
for


Drugs from biotechnology
processes, such as genetic engineering;

advanced
-
therapy medicines, such as gene
-
therapy, somatic cell
-
therapy
or tissue
-
engineered medicines
;


intended for the treatment of HIV/Aids, cancer, diabetes,
neurodegenerative disorders, autoimmune diseases and other immune
dysfunctions, or viral diseases
;


orphan medicines

If
emea

and EC approve u can market it in all
eu

participant countries

ANDA

356 h

Suitability petition

502j

505b(1)

505b(2)

OTC

DESI

DESI NOOH

Market till notice result

effective

Sec. 310.545
Drug
products
containing
certain active
ingredients
offered over
-
the
-
counter
(OTC) for
certain uses

in 21 CFR 310,
section 502 of the
Code of Federal
Regulations. Drugs
listed in this section
are categorically
considered new
drugs. In other
words, these
products cannot be
marketed under the
OTC monograph
pathway.

Monograph
applicable

Other methods:

monograph deviation

Time method

Approval
:

Triax

Pharmaceuticals

submitted

a

suitability

petition

as

follows
:


RLD
:

Retin
-
A

(
Tretinoin
)

Cream,

0
.
025
%
,

0
.
05
%
,

and

0
.
1

%
,

Johnson

&

Johnson


Proposed

Change
:

two

intermediate

strengths

0
.
0375
%

and

0

.
075
%


Basis

for

Approval
:

The

Agency

has

determined

that

sameness

of

therapeutic

effect

for

these

two

interim

strength

Tretinoin

Cream

products

can

be

demonstrated

using

comparative

bioavailability

data



Denial
:

Lachman

Consultant

Services

submitted

a

suitability

petition

as

follows
:


RLD
:

UltramB

(
Tramadol

Hydrochloride)

Tablets,

50

mg,

Ortho
-
McNeil

Pharm
,

Inc


Proposed

change
:

Tablets

to

Oral

Solution


Basis

for

denial
:

(a)

PREA
.


UltramB

is

not

labeled

for

pediatric

use
;

clinical

studies

would

be

required

and

(b)

clinical

trials

needed

for

oral

solution

due

to

uncertain

pk
/pd

relationship

BDSI’s
buccal

fentanyl

505(b)(2) NDA approved

The
buccal

fentanyl

product received approval based on
pk

and two Phase III
studies.


the
summary of the 2 Phase III studies (BEMA was the former trade
name, now ONSOLIS (TM
))

For their efforts, BDSI will be getting a princely sum of money.


BDSI had licensed the
product to
Meda

for milestone and royalty payments.


On 7/22,
BDSI announced

it
had received a $26.7 million milestone payment and would be entitled to double
-
digit royalty payments plus $30 million upon achievement of sales objectives.

The 505(b)(2) applicant may qualify for 3 or 5 years of market
exclusivity, depending on the extent of the change to the previously
approved drug and the type of clinical data included in the NDA. This
distinguishes a 505(b)(2) from an ANDA, where exclusivity can be
held for only 180 days. A 505(b)(2) application may also be eligible
for orphan drug or pediatric exclusivity.

A product approved via the 505(b)(2) pathway may receive an “AB”
substitutability rating in the Orange Book. Thus, from a therapeutic
substitution perspective and under state formulary laws, the 505(b)(2)
applicant is not disadvantaged relative to a generic (ANDA) drug

Article 10 of Directive 2001/83/EC

where

the

bioavailability

studies

cannot

be

used

to

demonstrate

bioequivalence
;

the results of tests and trials must be consistent with the data content
standards required in the Annex to the Directive 2001/83/EC as amended
by Directive 2003/63/EC. These applications will thus rely in part on the
results of pre
-
clinical tests and clinical trials for a reference product and in
part on new data.”

Stability Batches


BE Requirements
-

e.g. Sustained Release Product




US
:





EU / Australia
:









Fasted and/or Fed



Fasted









+ Fed








+ Steady State




Even after this there are many hurdles

PSURs

Type 1 A/B Variations

Type 2 A/B Variations

Coordination with Agencies

Type IA variations are minor changes

Notify

Admin changes

Changes that can be implemented within 14
days of notification.

Type IB variations are more scientific minor
changes and
implicit approval is granted within
30 days of notification
.

Type II variations are major changes

prior
-
approval, CBE
(immediate), CBE
-
30 and
annual report

Prior
-
approval (major
change):Substantial
potentialto

adversely affect
the identity, strength,
quality, purity, or potency of
a product

moderate change CBE

Minor change annual

changes that have
upcome

Readability tests

impurity

organic

inorganic

Residual solvents

genotoxic

Analytical validations

characterization

Stability changes

Eg

acetone solvent. Degradation changes

GMP deficiencies found in
indian

companies in 2006

Now this is the product I wish to market

, a pro
-
drug of
naproxen


Dsnt

increase
bp


And has
gastrointestinal profile than naproxen
with the same efficacy.

naproxcinoid

is metabolized to the NSAID naproxen

+

nitrate
butanediol

mononitrate

(BDMN)



subsequent downstream metabolites [gamma
-
hydroxybutyric

acid (GHB) and
butanediol

(BD)].


BDMN is the moiety responsible for donating nitric oxide
(NO).


I have done 35

studies also




NO is thought to stimulate GI protective factors that are
negatively affected by NSAIDs, such as mucus production,
secretion of bicarbonate and increased blood
-
flow in the gastric
mucosa

I can further extended application to hypertensive patients also

To show improved gastrointestinal safety, conducted three (3)
endoscopy studies in (2) healthy subjects and (1) osteoarthritis
patients. Note that just prior to the Advisory meeting
NicOx

had asked
to withdraw the ulcer claim. The studies are presented in the following
table:

in general,
fdarecommends

study durations of at least 6
months; The prescription proton pump inhibitors currently
marketed for this indication,
esomeprazole
,
lansoprazole
, and
the naproxen/
lansoprazole

combination product, were
supported by studies of 3 months and 6 months duration


Thus, the reviewer noted that studies 0002 and 0027 did not
use endpoints or duration consistent with studies used for
approval of PPI's. Study 0005 was reviewed with the caveat
that it was only 6 weeks (not months) duration. The
comparison of incidence of ulcers in this short study gave a
point estimate (
naproxcinod
/naproxen) of 0.70 (95% CI,
0.48, 1.03) p=0.07. The results were not significant and the
difference was judged to be not clinically meaningful.

I emphasized in the text above that the FDA used criteria that
were used for PPI product

approval.
NicOx

didn't want
treatment but just wanted labeling that showed show an
improvement.

The reviewer from FDA's Division of Gastroenterology Products outlined the following
study criteria used for

approval

(emphasis mine) of products (e.g., PPIs) for the
reduction of NSAID

-
induced ulcers:

Naproxcinod

represents an additional treatment option for physicians and OA
patients, combining the proven efficacy and safety of naproxen with an NO
-
donating moiety that mitigates some of the known side effects of NSAIDs.
Naproxcinod

is less likely to increase BP than NSAIDs, which may be of
particular importance to OA patients with pre
-
existing hypertension. The
overall benefit/risk profile of
naproxcinod

750 mg

bid

and 375 mg

bid

is
positive and supports its use for the relief of the signs and symptoms of OA.”
As I summarized above, FDA’s analysis of the BP data indicated that
naproxcinod

was not sufficient to

I emphasized in the text above that the FDA
used criteria that were used for PPI
product

approval. I

didn't want treatment but
just wanted labeling that showed show an
improvement.

Here is the broader issue for us in the 505(b)(2)
world: we are developing improvements to
existing products and in order for them to be a
commercial success we must be able to promote
the difference from what is often the generic RLD.
In order to be able to legally promote a difference,
the data must be on the label. What studies are
sufficient to be included in the label? Do the data
need to show clinically meaningful difference (an
objective standard) or simply statistically
different? Does the answer to the latter question
depend on which section of the label we want to
have modified? I’m uncomfortable leaving
questions unanswered at the end of this posting,
but the general answer is, it depends on each
circum
stance.

Thank you for your patient hearing