“TO SIN BY SILENCE WHEN THEY SHOULD PROTEST MAKES COWARDS OF MEN”       – Abraham Lincoln

The ghost of untested, irrational and even of bizarre kind of Fixed Dose Combination (FDC) drugs, which continue to be launched, promoted, prescribed and sold freely across the length and breadth of India, has started haunting the Ministry of Health of India, yet again, in 2013. 

Though the issue originated decades ago, in 1988 appropriate ‘Rule’ of the Drugs and Cosmetics Act of India was amended suitably to have a firm regulatory grip over this situation. Despite this much awaited amendment, the situation almost went astray with incessant market entry of a large number untested FDC medicines of dubious medical rationale.

A free for all situation, as it were, in the FDC arena, continued to be facilitated by blatant laxity on the part of, especially, the state drug regulators by allowing unfettered market entry of such drugs, ignoring the CDSCO directive.

On the other hand, the Central Drugs Standard Control Organization (CDSCO), despite its statutory powers,  continued to suffer from humongous inaction untill the issue resurfaced again in 2007 and then of course, now in 2013.

The WHO Model:

The 2005 ʹProcedure to update and disseminate the WHO Model List of Essential Medicines, Criteria for Selection’ includes the following statement regarding Fixed Dose Combination products (FDCs):

ʺMost essential medicines should be formulated as single compounds. Fixed‐dose combination products are selected only when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety, and adherence or in delaying the development of drug resistance in malaria, tuberculosis and HIV/ AIDS.ʺ

Thus, FDCs:

• Need to demonstrate clinical efficacy and safety beyond the individual drugs when given alone.

• Need to ‘demonstrate bioequivalence of the single combined dose unit with the components administered in the same doses separately but concomitantly’.

‘Adherence’ aspect of WHO Model for FDCs is also important. Problems with ‘adherence’ could lead to inadequate and inconsistent dosing, which in turn could lead to development of drug resistance.

With robust and unquestionable medical rationale, FDCs are expected to provide superior efficacy and improved compliance without causing any untoward risk to patients.

A major disadvantage:

However, one of the major disadvantages with the FDCs is lack of flexibility in adjusting dose of individual ingredients, even if it is required for some patients. Internationally, most popular example is the FDCs of antiretroviral drugs for HIV infected patients like, Combivir, Trzivir, Kaletra etc.

Interestingly, in India there are FDCs for almost all disease areas from allergic disorders to Wolf-Parkinson-White syndrome (exaggerated), as it were.

Market attractiveness for FDCs in India: 

The domestic market for FDCs is very large and growing much faster, in sharp contrast to the western world. The following table will vindicate this point:

% Share
Drug	2008	2009	2010	2011
Plain	55	55	55	54
Combinations	45	45	45	46
Domestic Market: USD 13 Billion; MAT Apr 2013

Source:IMS

Thus, because of growing market demand, pharmaceutical companies in India tend to market FDCs of all different permutations and combination, at times even crossing the line of any ‘sound medical rationale’. For this reason, we find in the website of ‘Central Drugs Standard Control Organization’ (CDSCO), the banned list of so many FDCs.

A messy regulatory situation:

Introduction of new FDCs does not only warrant a ‘sound medical rationale’ but also ‘strict conformance to all prescribed regulatory requirements’ for patients’ interest. 

To check unfettered market introduction of potentially harmful FDCs, the Ministry of Health issued a Notification in September 1988, including FDCs in Rule 122 E of the Drugs & Cosmetics Rules (D&CR) 1945.

In effect, it removed the powers of the State FDAs to give manufacturing or marketing approval of FDCs. After the notification was issued, all manufacturers/marketers of all new FDCs are required to apply only to the Drug Controller General of India (DCGI) under Rule 122E of the D&CR 1945 as a new drug, along with the stipulated fees by way of a Treasury Challan.

Since this entire process entails appropriate regulatory data generation, besides  time and expenses involved, the above ‘Rule’ was continuously and deliberately broken and manufacturing and marketing approvals for various types of FDCs falling under ‘new drug’ category were regularly sought and granted by the State Drug Controllers.

Many believe that the State FDAs were equally responsible for knowingly flouting the Law, as were the pharmaceutical manufacturers.

Patients’ safety – the foremost concern:

Despite serious concerns expressed by a Parliamentary Standing Committee, this complicity resulted in the market being flooded with ‘irrational combinations’ which posed a real threat to patients’ interest and safety. The State FDAs were reminded of the notification by the earlier DCGI.

294 FDCs were banned by the DCGI in 2007. Thereafter, the important issue of patients’ interest and safety got converted into a legal quagmire, as many FDC manufacturers chose to go to the court of law to protect their business interest and also managed to obtain a ‘Stay’ order from the Madras High Court. The matter is still subjudice.

Be that as it may, those 294 FDCs banned by the Ministry of Health of India on health and safety grounds continue to be promoted, prescribed and sold to patients across India without any hindrance, whatsoever.  

Untangling the messy knot:

As the issue got entangled into prolonged litigations, the CDSCO took initiative of resolving this contentious issue again in 2009 with the help of an expert committee, involving the manufacturers.

This subcommittee cleared 48 FDCs under ‘similar FDCs already approved’, after discussing the merits and demerits, including pharmacodynamics, pharmacokinetics, side effects, dosage, medical rationale etc. of each ingredient and the combinations. The decision of the Sub Committee was then submitted to the Drug Technical Advisory Board (DTAB).

After formal approval of DTAB, these combinations are construed to be new drugs and any company wishing to market/manufacture the formulation would require submitting its Application in Form 44 to the DCGI to get approval in Form 45.

This decision was expected to send a clear signal to all concerned that resorting to any form of shortcuts to bypass strict adherence to prescribed regulatory requirements, could seriously jeopardize patients’ interest and safety. The same process was subsequently followed for the balance 142 FDCs, as well.

Thereafter, a special committee was again appointed by the CDSCO in 2013 to look into this matter in a holistic way. However, such sporadic knee-jerk reactions have failed to deliver any tangible results in this area – not just yet.

The saga continues:

Even after the above critical decision of the DTAB the saga still continues.

In March 2013, by a written reply, the Minister for Health and Family Welfare reportedly informed the Lok Sabha (the lower House of the Parliament) that in twenty three cases of new FDC, licenses have been granted by the State Licensing Authorities (SLAs) without the mandatory approval of the DCGI and action will be taken in all these cases.

However, no one seems to know, as yet, what action the Government has taken against those errant officials.

Current scenario:

Recently, the Directorate General of Health Services (DGHS) by a notification to State Drug Controllers has reportedly ordered all manufacturers of new FDC products, licensed locally before October 2012 without CDSCO permission, to submit safety and efficacy data prior to 30 August 2013.

This decision of DGHS has created a furore within the concerned FDC manufacturers, yet again, the possible outcome of which is yet to be ascertained.

The State Drug Controllers had issued manufacturing licenses for these FDCs prior to October 2012. At that time concerned manufacturers were given 18 months time period to prove efficacy and safety of these medicines to the DCGI. Regrettably, as per the above report, the DCGI has confirmed that he has received hardly any response from the FDC manufacturers till date on this regulatory requirement.

CDSCO has also stated that manufacturers, who will fail to submit the required data by the deadline run the risk of having their products banned from the market.

Before this, the State Drug Controllers were informed about this requirement on January 15, 2013.

At this point it is worth mentioning, the DCGI in October 2012 had reportedly also barred the State Drug Controllers from granting manufacturing licenses to pharmaceutical companies under brand names of the drugs, directing them to strictly issue licenses under generic name of the molecule. Additionally, he also asked the state licensing authorities not to grant licenses to combination drugs, which are technically ‘new drugs’ and fall within the domain of DCGI only.

Conclusion:

This logjam with FDCs certainly cannot continue in perpetuity, neither should such regulatory sloppiness be acceptable to any right thinking stakeholder.

All blatant violations of Drugs and Cosmetics Act of India must be stopped forthwith and the violators be brought to justice without delay. Patients’ health interest, as required by the drug regulators, is non-negotiable.

The order of DGHS asking all manufacturers of new FDCs, licensed locally before October 2012 without CDSCO permission, to submit safety and efficacy data prior to 30 August 2013, should not follow recently reported Pioglitazone type of volte face, once again, under similar outside pressure.

It is high time now for the Government to bring the unending saga of  irrational and harmful FDCs, orchestrated by defiant manufacturers, encouraged by sloppy regulators and catalyzed by humongous systemic inaction, to its logical conclusion, for patients’ sake. 

By: Tapan J. Ray

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.