|Year : 2019 | Volume
| Issue : 3 | Page : 138-142
A questionnaire-based study to assess the status and perspective of fixed-dose combination among the various stakeholders including regulators, clinicians, researchers, and industry
Krishan Kumar Bhardwaj1, K Bangarurajan2, Tanveer Naved2, Satyendra Kumar Rajput3
1 Central Drugs Standard Control Organization, Ghaziabad; Central Drugs Standard Control Organization, Ghaziabad, Director General of Health Services, MoHFW, Government of India, New Delhi, India
2 Central Drugs Standard Control Organization, Ghaziabad, Director General of Health Services, MoHFW, Government of India, New Delhi, India
3 Center for Pharmacology and Toxicology, Amity Institute of Indian System of Medicines, Amity University, Noida, Uttar Pradesh, India
|Date of Web Publication||2-Jul-2019|
Mr. Krishan Kumar Bhardwaj
Center for Drug and Regulatory Affair, Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Fixed-dose combinations (FDCs) dominating the global market because of better compliance. However, irrational combination can lead to human-made menace in terms of development of resistance, tolerance, drug abuse, and economy encumbrance. The US Food and Drug Administration defines a combination product as “a product composed of any combination of a drug and a device or a biological product and a device or a drug and a biological product or a drug, device, and a biological product.” Unfortunately, many FDC being introduced in India are usually irrational. The need for the present study arises as the Indian drug regulatory system has been oscillating between central drug authorities versus state drug regulatory authorities. To assess the same fifty-six regulators and 70 other stakeholders including researchers, clinician, and industry people have exposed to 14 questions, and the same are used to get the insights of FDC among producers and consumers. All data were analyzed using Sigma plot Software. Data was presented in the form of percentage of response (responders vs. nonresponders, agree vs. disagree, yes vs. no). Most of the stakeholders (99%) stressed on Rule 122 to be strictly followed and same should be disseminated among all the stakeholders. Similarly, it was emphasized by more than 95% stakeholders that FDC contents should be tested as per official pharmacopoeia.
Keywords: Act, approved combinations, Central Drugs Standard Control Organization, court, drugs, new drugs, nonapproved fixed dose combination, Rule 122D, Rule 122E, Rule 21
|How to cite this article:|
Bhardwaj KK, Bangarurajan K, Naved T, Rajput SK. A questionnaire-based study to assess the status and perspective of fixed-dose combination among the various stakeholders including regulators, clinicians, researchers, and industry. J Adv Pharm Technol Res 2019;10:138-42
|How to cite this URL:|
Bhardwaj KK, Bangarurajan K, Naved T, Rajput SK. A questionnaire-based study to assess the status and perspective of fixed-dose combination among the various stakeholders including regulators, clinicians, researchers, and industry. J Adv Pharm Technol Res [serial online] 2019 [cited 2019 Sep 16];10:138-42. Available from: http://www.japtr.org/text.asp?2019/10/3/138/261970
| Introduction|| |
A multipronged corrective approach involving regulators, academia, industry, clinician, and public is needed to correct the dismal fixed-dose combination (FDC) scenario globally. FDC are combinations of two or more active drugs in a single dosage form as per Drugs and Cosmetics Rules and also US Food and Drug Administration defines a combination product as “a product composed of any combination of a drug and a device or a biological product and a device or a drug and a biological product or a drug, device, and a biological product.”
FDC states the combination of two or more than two drugs together to achieve the synergistic effect or patient convenience or compliance then it is called as FDC. A FDC is considered as a new drug in India and requires approval from the Central Drugs Standard Control Organization (CDSCO) Office,, Nowadays, it is dominating the global market because of better compliance. DCG (I) has approved 1271 v drugs since 1961 till October 9, 2017 in India.
Looking at the current scenario, many industries have started combining the ingredients without even taking the approval from the CDSCO office and without doing sufficient Clinical Trials, Pharmacokinetics and Pharmacodynamics studies. However, they have received the licenses from the State Licensing Authorities and start manufacturing and marketing the FDCs in the country.
In Oct. 2012, Central Drugs Standard Control Organization office also issues the instructions to the State Licensing Authorities for not issuing any license to any company for the FDCs which are not approved by the Central Drugs Standard Control Organization Office. Under Public interest and for the Health Benefits of Patients State Licensing Authorities are not allowed to issue the licensees for FDCs which are not approved by the CDSCO Office.,
In June 2013, CDSCO Office came up with the notification and asked the applicants to submit the applications for proving the rationality, safety, and efficacy of the FDC's marketed in the country without approval from the CDSCO Office.,
CDSCO office also formed a committee called “Kokate Committee” to evaluate the rationality, safety, and efficacy of the FDC's.
Kokate Committee evaluated the FDC applications filed by various manufacturers and categorize the products into four categories:
- Category A – Grossly irrational
- Category B – Further deliberation/data is required to prove the safety and efficacy of the FDC
- Category C – Rational FDC's
- Category D – Phase IV study is required.
Still the current challenge faced by the CDSCO Office is that the many nonapproved FDCs are still available in the market. The present study is an attempt to understand the acceptability of the FDC's which are manufactured and marketed in the country without due approval from the DCG (I). The present study aims to create awareness and knowledge so as to know the opinion and perspectives of the stakeholders including regulators, researchers, clinician, and industry people.
| Materials And Methods|| |
This was a cross-sectional questionnaire-based study carried out among various stakeholder including researchers, clinician and industry people. One hundred and twenty-six stakeholders participated in this study. The questionnaire was designed and tested among small groups for doing a pilot study. The modified questionnaire was given to all participants. The questionnaire having 14 important questions/comments was given to participants after explaining the purpose of the study [Table 1]. Any doubts regarding questionnaire were clarified by the investigators. Thirty minutes was given for filling the questionnaire. The response in terms of responders versus nonresponders, agree versus disagree, yes versus no was recorded and analyzed by descriptive statistics using Sigma Plot software (Systat Software, Inc., San Jose, USA).
|Table 1: Questionnaire to assess the perspective of fixed dose combination among various stakeholders including researchers, clinician and industry people|
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Format of questionnaire as given below
Questionnaire is related to FDC which is not yet approved by DCG(I) for manufacturing and marketing in the country and falls under the category of “new drug.” No new drug shall be manufactured for sale unless it is approved by the Licensing Authority as defined in clause (b) of Rule 21 of Drugs and Cosmetics Rules, 1945. As per Rule 122D of Drugs and Cosmetics Rules, 1945, an application for permission to import or manufacture FDC of two or more drugs as defined in clause (c) of Rule 122E shall be made to the licensing authority as defined in clause (b) of Rule 21 in Form 44.
| Results and Discussion|| |
There were 14 questions to understand the status and perspective of FDC among producers and consumers. About 98.2% of regulators, 90% of researchers, 85% of clinicians and 90% of industry people were found to be of the opinion that Rule 122D and 122E is not only meaningful but also of utmost importance for Indian Pharmaceutical market of FDC [Table 2]. They have also expressed that DCG(I) approval is to be mandatory for any permission granted by state licensing authority (SLA). SLA is responsible for giving the license of manufacturing site for drugs including active pharmaceutical ingredients and finished formulation, licensing of establishment for sale or distribution of drugs, approval of drug testing laboratories, monitoring of quality of drugs and cosmetics marketed in the country, investigation and prosecution in respect of contravention of legal provision and recall of substandard drugs. The major function of CDSCO includes under the Drug and Cosmetics Act, the regulation of manufacture, sale and distribution of Drugs is primarily the concern of the State authorities, while the Central Authorities are responsible for approval of new drugs, Clinical Trials in the country, laying down the standards for drugs, control over the quality of imported drugs, coordination of the activities of State Drug Control Organisations, and providing expert advice with a view to introduce uniformity in the enforcement of the drugs and cosmetics act and drug controller general of India is responsible for approval of licenses of specified categories of drugs such as blood and blood products, intravenous fluids, vaccine, and sera. In any case if D and C rules are not followed than 70% of regulators, 58% of researchers, 60% of clinicians and 80% of industry people in opinion that defaulters should be punished as per Se ction 27 D of Drugs and Cosmetics Act 1940.
|Table 2: Responses from various stakeholders regarding fixed dose combinations|
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The mixed response received from various stakeholders could be because of their belief that such FDC are in practice from the past 20 years without any reported adverse effect. However, regulators mentioned that stringent punishment should be incorporated in the governing rules for proper implementation of procedures required for FDC market. Regarding the same appropriate initiatives to be suggested by DCG(I) and SLA. Most of the regulators (92.8%), researchers (77.5%), clinicians (70%), and industry people (70%) expressed the need of such initiatives [Figure 1]. Considering the facts that several limitations exist including an availability of reference standard and testing procedures in pharmacopoeias. Such kind of limitation needs to be taken care by regulatory authorities so that unfortunate exponentially growing FDC market in India can be curtailed. As healthcare is primary concern for all the stakeholders including producers, consumers, regulators as well as judiciary. Our courts,,, are very sensitive and sincere for giving the director to all stakeholder for implementation of Drugs and Cosmetics Act 1940 and rules 1945 thereunder.,
|Figure 1: Percentage of response from various stakeholders regarding the fixed-dose combination's|
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| Conclusion|| |
The stakeholders are of the view that FDCs are very important in terms of compliance, as they facilitate the medicinal usage. Therefore, it is of utmost importance that FDCs should be strongly regulated and in no case, there should be any FDC available over the counter without DCG (I) approval. The regulator should come up with stringent draft policy to stop such menace from happening in future. In addition, it is also an obligation for the regulator to come up with a well prescribed abridge clinical requirement in case of right rationale combination which might not be available overseas. Therefore, the present study recommends the use of rationale FDC with proper approval and permission from regulatory bodies CDSCO and SLA.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Rule 122 D, Appendix VI of Schedule Y under Part X-A of Drugs and Cosmetics Act 1940 and Rules 1945 thereunder.
Central Drug Standards Control Organization. Report of Expert Committee on Fixed Dose Combinations (FDCs) Licensed by SLAs for Manufacture Without Approval of DCG (I), Applications of Which Received by CDSCO; 2015. Available from: http://www.cdsco.nic.in/writereaddata/fdcexpert%2019.1.2016.pdf
. [Last accessed on 2016 Jun 18].
Central Drug Standards Control Organization. Prohibition of Fixed Dose Combination Drugs for Human Use Under Section 26A of Drugs and Cosmetics Act, 1940. Central Drug Standards Control Organization; 2016. Available from: http://www.cdsco.nic.in/writereaddata/SKM_12-03-2016.pdf
. [Last accessed on 2016 Jun 18].
Central Drug Standards Control Organization. Report of Expert Committee on Evaluation of Cases of Fixed Dose Combinations (FDCs) Considered as Irrational and Where Show Cause Notices were Issued to the Applicants to Submit their Replies. Central Drug Standards Control Organization; 2016. Available from: http://www.cdsco.nic.in/writereaddata/fdcreport10_2_2016.pdf
. [Last accessed on 2016 Jun 18].
Central Drug Standards Control Organization. Notice Dated. Examination of Safety and Efficacy of FDCs Licensed for Manufacture for Sale in the Country without Due Approval from Office of Drugs Controller General, Central Drug Standards Control Organization; 17 June, 2015. Available from: http://www.cdsco.nic.in/writereaddata/notice%20letter17_6_2016_2016.pdf
. [Last accessed on 2016 Jun 18].
McGettigan P, Roderick P, Mahajan R, Kadam A, Pollock AM. Use of fixed dose combination (FDC) drugs in India: Central regulatory approval and sales of FDCs containing non-steroidal anti-inflammatory drugs (NSAIDs), metformin, or psychotropic drugs. PLoS Med 2015;12:e1001826.
Gupta YK, Ramachandran SS. Fixed dose drug combinations: Issues and challenges in India. Indian J Pharmacol 2016;48:347-9.
] [Full text]
Gautam CS, Saha L. Fixed dose drug combinations (FDCs): Rational or irrational: A view point. Br J Clin Pharmacol 2008;65:795-6.
[Table 1], [Table 2]