FIXED DOSE COMBINATIONS REGULATORY REQUIREMENTS IN INDIA AND THE RECENT BAN OF FDCs

1. An Overview of Fixed Dose Combinations and
Regulatory Requirements in INDIA
Submitted By,
V JAYA PRAKASH,
(Regd. No:218311).
Shri Vishnu College of Pharmacy (Autonomous)
Affiliated to Andhra Univ., Visakhapatnam; Approved by AICTE and PCI, New Delhi, and recognised by APSCHE
1

2. Shri Vishnu College of Pharmacy (Autonomous)
Affiliated to Andhra Univ., Visakhapatnam; Approved by AICTE and PCI, New Delhi, and recognised by APSCHE
Aim
To discuss about fixed dose combinations and its regulatory
requirements in India, US, and EU.
Objectives
 To provide regulatory requirements regarding FDCs in India,
US, and EU.
 To demonstrate the clinical trial requirements.
 To address the bioavailability and bioequivalence data
requirements.
 To address the reasons for banning of the FDCs in India.
 To provide an overview on FDCs.
2

3. INTRODUCTION
• Fixed-dose combination drugs (FDCs) are formulations that
contain two or more active ingredients in a single dose.
• More than one medication is as often as possible used for
treatment of either single disease or multiple disease conditions.
• The FDCs formulation may have up to five or even more drug
ingredients with or without rationality of their presence and in
the quantity.
3

4. • These medicines are formulated to have a similar
bioequivalence of the two different drugs as separate medicine
and therefore have similar pharmacokinetics and
pharmacodynamic effects, as well as reducing the dose- related
side effects of a single drug.
• FDCs are classified into four types according to their
regulatory status.
4

5. • The fixed-dose combinations are usually used for
cardiovascular diseases (hypertension, hypercholesterolemia),
diabetes, infectious diseases (Helicobacter pylori, AIDS- HIV
infections and tuberculosis), psychiatric disorders (depression
and Alzheimer’s) and respiratory diseases (asthma and COPD)
including allergies and in the fields of ophthalmology and
dermatology.
5

6. CLASSIFICATION
6
Not marketed in India and one or more active pharmaceutical ingredients is a
new drug not approved in India
Market in India but some changes are sought
• IIIA: Change the ratio of active pharmaceutical ingredients and the doses of
the individual components are within the approved dose range for the
individual drugs
• IIIB: Make a new dosage form and/or a new route of administration for the
same indication
Category i
Category ii
Category iii
• Not marketed in india and one or more active pharmaceutical
ingredients is a new drug not approved in india
Category iv
Not marketed in India but the active pharmaceutical ingredients are
approved/marketed individually
• IIA- marketed abroad
• IIB- Not marketed anywhere but individual APIs used

7. ADVANTAGES OF FDCS
 Lower doses and fewer side effects
 Early treatment targets
 Better compliance
 Lower administrative cost
 Target infectious agents rather than body tissue
 Combination of products lines as well as therapies
 Patent extension
7

8. DISADVANTAGES OF FDCS
 Pharmacokinetics mismatch and having peak efficacy at
different time.
 Chemical incompatibility leading to decreased shelf life.
 Its therapeutic efficacy has not been proved scientifically.
 Drug interactions because of the common metabolizing
pathways .
8

9. INDIAN RULES
• Drugs in India are regulated by the Drugs and Cosmetics Act
1940 and the Drugs and Cosmetics Rules 1945.
• Imports and marketing of new drugs are controlled nationally
by CDSCO, while manufacture, distribution and sale of drugs
are the responsibility of the States.
• ‘New drugs’ as a category of ‘drugs’ was first introduced into
the Rules in 1952, and FDCs were expressly mentioned as a
specific subcategory of new drugs in 1988.
9

10. REGULATORY PROVISIONS FOR FDCS IN
INDIA
• Appendix VI of Schedule Y (Drugs & Cosmetics Rules 1945,
India) provides details about the requirements for
manufacture/import approval and marketing of various types
of FDCs.
• As per the Rule 122E of Drugs and Cosmetics act 1940, the
fixed dose combination (FDCs) is considered as New Drugs
and the Central Drugs Standard Control Organization
(CDSCO), after due examination of data on rationality, safety,
efficacy and issues approval.
10

11. CLINICAL DATA REQUIREMENTS
a. Clinical studies to be intended to figure out whether the
combination has an advantage over the single active
components.
b. The study should be conducted in the appropriate patient
population with an adequate sample size.
c. The studies should be planned so that there is regional
representation to all populations in the country.
11

12. d. The sites should be approved by the DCGI .
e. Sites should have Institutional Ethics Committees registered
with the CDSCO.
f. The data should preferably demonstrate that each active
compound should contributes to the therapeutic effect of the
combination.
g. The choice of comparators for the purpose of safety and
efficacy studies.
12

13. • Clinical trials must be carried out in India on ‘new drug
substances discovered in India’ from phase I or from phase III
if ‘discovered’ outside India.
• The 1988 rules specified the minimum numbers and ranges for
trial participants and sites.
13

14. Trial phase 1988 Schedule Y 2005 Schedule Y
Phase II ‘Normally 10–12 patients should be
studied at each dose level. These
studies are usually limited to 3–4
centres.
Studies in Phase II should be
conducted in a group of patients
who are selected by relatively
narrow criteria leading to a
relatively homogeneous population.
These studies should be closely
monitor.
If the application is for conduct of
clinical trials as a part of multi-
national clinical development of the
drug, the number of sites and the
patients as well as the justification
for undertaking such trials in India
shall be provided to the Licensing
Authority.
14

15. Trial
phase 1988 Schedule Y 2005 Schedule Y
Phase III If the drug is already
approved/marketed in other countries,
phase III data should generally be
obtained on at least 100 patients
distributed over 3–4 centres in Indian
patients.
 If the drug is a new drug substance
discovered in India, and not marketed
in any other country, phase III data
should be obtained on at least 500
patients distributed over 10–15 centres.
For new drugs approved out
side india ,Phase III need to be
carried out primarily to generate
evidence of efficacy and safety of
the drug in Indian patients.
Prior to conduct of Phase III
studies in Indian subjects,
Licensing Authority may require
pharmacokinetic studies to be
undertaken to verify that the data
generated in Indian population is
in conformity with the data
already generated abroad.
15

16. Trial
phase 1988 Schedule Y 2005 Schedule Y
Phase IV* In addition, data on adverse
drug reactions observed
during clinical use of the
drug should be collected in
1000–2000 patients.
Post Marketing trials are studies
(other than routine surveillance)
performed after drug approval.
16

17. DATA REQUIREMENTS FOR APPROVAL OF
FIXED-DOSE COMBINATION
1. Form 44
2. Treasury Challan
3. Justification as Annexure 1
4. Source of bulk drugs
5. Strategies towards PMS as Annexure 4
6. Scientific literature supporting the claim as Annexure 2
7. Risk benefit assessment of combination
8. Regulatory approval for the APIs
9. Regulatory approval of FDC
10. Free sale certificate from the country of origin
17

18. 11. Complete chemical and pharmaceutical data of FDC
12. GMP certification of manufacturing plant
13. Certificate of analysis of study drug(s)
14. Copy of proposed package insert
15. Copy of package inserts and promotional literature
16. Clinical and non-clinical study reports
17. Reports of bioequivalence studies as Annexure 7
18. Acute and sub acute toxicity data in case of injectable
formulation
19. In-vitro studies data
18

19. CONDUCT OF BIOAVAILABILITY
(BA)/BIOEQUIVALENCE (BE) STUDIES
General
• Bioequivalence studies are required for FDCs in category.
• IIA, IIB, in vitro data for IIIA, IIIB and IV.
• Data on absolute bioavailability shall be required in category I
and III, i.e. comparison of the area under the curve for plasma
concentration over time.
19

20. Title of the study, the protocol code.
Name of the Investigational product tested, development
Phase, indication studied.
A brief description of the trial design.
The start and end date of patient accrual.
The start and end date of sample analysis.
The names of the Sponsor and the participating Institutes
(Investigators).
Names and batch numbers of the products compared
20

21. Pharmacovigilance for FDCs
• This will be applicable for safety monitoring of the FDCs.
Pharmacovigilance of the FDCs will operate under the PvPI.
• It needs to be done throughout the life cycle of the product.
1. Sponsors will have to submit a detailed pharmacovigilance plan
along with marketing authorization application.
2. Pharmacovigilance plan should mention
a. Safety data from clinical development
b. All the potential risks of an FDC
21

22. c. Summary of anticipated risks
d. Population at risk and
e. Situations not adequately studied
f. All the potential drug
drug and drug – food interactions of the FDC either as a
separate document with pharmacovigilance plan or
pharmacovigilance strategies or in the section referring to
safety specifications of the Common Technical Document
(CTD)
22

23. CASE STUDY
The Ministry of Health and Family Welfare has recently
prohibited the manufacture for sale, sale or distribution for
human use of 328 FDCs through the powers conferred by section
26A of the Drugs and Cosmetics Act, 1940.
Background
 In March 2016, Central Government had prohibited the
manufacture for sale, sale, and distribution for human use of
344 FDCs.
 However, drug manufacturers dragged Central Government to
court over its order.
23

24.  As per the directions given by the Supreme Court in December
2017, the matter was examined by the Drugs Technical
Advisory Board (DTAB).
 The Drugs Technical Advisory Board recommended that there
is no therapeutic justification for the ingredients contained in
328 FDCs and these FDCs may involve risk to human beings.
24

25. REASON FOR THE BAN OF FDC DRUGS
The CDSCO gave three main reasons for the ban: The drugs
were:
1. “Likely to involve risk to human beings”
2. “There are safer alternatives available in the
market.”
3. “Found to have no therapeutic justification”
25

26. SUCCESS FACTORS FOR FDC PRODUCTS
Formulation Development challenges
• A variety of issues potentially exist when combining two or
more molecule.
• It is not as easy as combining two or more molecule in a tablet
press or capsule.
• It is very important to understand the mechanism of action,
chemistry of each component as well as drug substance
preformulation characteristics also very important.
26

27. • Below is the just few formulation consideration.
• Release profile differences
• Incompatibility
• Delivery Challenges
• Particle size
• Regulatory requirement
27

28. PATENT FEASIBILITY
• The criteria for that product should be innovative and show
functionality. Patent are granted on following criteria;
• Must be novel i.e. not publically known.
• Must be inventive i.e. not obvious over what was already
known.
• The more successful combination products typically focus on
unmet medical needs.
28

29. PHYSICIAN CONSIDERATIONS
• Many physicians prefer to select relative dosing of
combination components on the basis of individual patient.
• Patients may potentially be exposed to drugs they do not really
need conceptually, medication management & compliance
should improve with patients. However, little evidence exists
regarding compliance improvement.
29

30. 30