Fixing the Right Dose
In a gap
of just six days, between 13 and 19 September, 2008, three news items – one
apparently contradicting another – caught the attention of the pharmaceutical
industry’s well-informed circle.
The first news came on the media on 13 September
informing the imposition of ban on 328 fixed-dose combination (FDC) drugs with
immediate effect by the Union Health Ministry.
The second news published in media on 17 September was
that the two-member bench of the Supreme Court comprising Justices R F Nariman
and Indu Malhotra had allowed the sale of four banned drugs which include Piramal
Healthcare’s Saridon, GlaxoSmithKline’s ‘Piriton’, Juggat Pharma’s ‘Dart’ and
one more. Within days, the apex court revoked the government’s order, at least
temporarily, following the challenge petition filed by the pharmaceutical
companies. The Supreme Court had also asked the Centre to file its reply on the
petition.
Further, on 19 September, the media reported that the
single judge bench of the Delhi High Court of
Justice Vibhu Bakhru issued a notice directing the government not to take any
coercive step against the pharmaceutical companies and their business
associates namely stockists or dealers for the available stocks of the banned
FDC drugs in the market. The writ petition, in this case, was filed by the
giant pharmaceutical companies like Glenmark, Lupin, and Mankind on the ground
that it was difficult for them to immediately recall banned drugs from across
the country. The Delhi High Court, meanwhile, has directed the Centre to file
an affidavit explaining the reasons. The next hearing would be on 9 October. Earlier,
the High Court allowed pharma major Wockhardt to sell its banned FDC drug ‘Ace Proxyvon’, on the plea that the company was not provided with
relevant information by the government’s agency.
The above developments raised serious questions about
the government’s health and pharmaceutical policies since the government is
engaged in firefighting in the court of law to safeguard its own order.
Secondly, will the banning of few FDC drugs be sufficient for public health
protection or should the government really concentrate to overhaul the drug
regulatory procedures? This article is pledged to find the justified answers.
Attempts shall be made to focus on certain basics so that the real answer does
not get lost in the web of rapid gabbling talk and technical jugglery, as is
usually the case, whenever questions are raised about healthcare and medicine.
What does FDC mean?
The nomenclature, FDC drugs, itself is confusing and
misleading. Fixed-dose combinations are actually the hotchpotch of two or more
active drugs in a single formulation. So, hereafter, we shall refer to as FDCs
only and, no more as the FDC drugs. The staggering statistics of the domestic
pharmaceutical market of India suggests that FDCs account for 50 per cent of
the sales while the overall market size is around Rs 1.18 lakh crore.
According to the “Directory of Pharmaceutical
Manufacturing Units in India 2007” published by the National Pharmaceutical
Pricing Authority (NPPA) of the Government of India, the Indian pharmaceutical
industry, with 10563 pharmaceutical manufacturers across the country, can be dichotomized
into two broad camps: bulk drugs and formulations. Out of them, 77.4 per cent
manufacture formulations and remaining 22.6 per cent are engaged in bulk drugs
manufacturing.
Bulk drugs are actually the active pharmaceutical
ingredients (APIs) which are used to manufacture the formulations. The formulations,
however, are the end-products of the medicine manufacturing process which are
available in the form of tablets, capsules, syrups, injectables etc.
Formulations should usually contain
only one bulk drug. But, there are a large number of formulations available
which contain more than one bulk drug. They are called FDC formulations and
their numbers are ever increasing in India. Thus, the FDCs are not the drugs
but actually the formulations.
It’s pretty expensive to launch a new bulk
drug and its formulation since it involves much scientific research and number
of multi-phase in-vitro as well as in-vivo trials which also have enormous
risks of failure. On the other hand, the FDCs are practically exempted from
such stringent requirements. However, the Indian drug regulators see a “new
drug” in any new FDC formulation made by combining two or more bulk drugs. In
such case, the formulator company has to submit only the proof of efficacy,
safety and bio-availability of the combined active ingredients of that FDC to
the government regulatory bodies. Though, such practice is usually prevalent
for the first few new formulators. A large number of pharmaceutical companies
in India do not have any obligation to prove their medicines’ utility before
making a new FDC available in the market.
Presumed advantages and disadvantages
of FDCs
Over a period of time, the pharmaceutical and
biomedical device industry has engaged itself in developing the methods of drug
delivery mechanism that rely on sustained release from a matrix or binder or
their structures that contain medication. Such sustained release dosage forms
are needed particularly for paediatric and geriatric medicines where repeated
dosages are disadvantageous. With this background, the pro-FDC lobby advocates
that the simpler dosage schedule of FDCs improve patients’ compliance and,
thereby, improve the treatment outcomes. They also argue that the FDCs reduce
inadvertent medication errors; procurement, management and handling of drugs
are simplified besides many other advantages like lesser side effects and
minimizing potential drug abuse.
However, the counter-arguments suggest that FDCs might
have potential quality problems when drugs are combined and sometimes the incompatible
pharmacokinetics between the drugs could make them irrational. Dosing with FDC is
inflexible and cannot easily be regulated as per the patient’s individual need
such as body weight, age, co-morbidity etc. If a patient is allergic to one of
the components of FDC, then the whole therapy has to be replaced by separate
drugs. Sometimes, drug interactions may also lead to alteration of the
therapeutic effect. Most importantly, FDCs are sometime more expensive than
separate formulations.
The
US experience of FDC
In
the wake of the thalidomide birth defect tragedies of early 1960s, the
Kefauver-Harris Drug Amendments of 1962 (Drug Amendments) was enacted which,
mentioning for the first time about compounded drugs, mandated that the drugs to
be safe as well as effective with respect to manufacturing claims, before they were
put in the market.
At
the beginning of the 1970s, combination drugs in the USA were accounted for over
half the pharmaceutical products and for 40 per cent of the best-selling drugs.
Since then, much controversy has been generated regarding their use; while some
physicians fiercely defended their right to prescribe combined preparations,
the regulatory authorities attempted to restrict their use. In the late 1960s,
a drug efficiency study was conducted in the USA by the National Academy of
Science and the National Research Council to review the efficacy of all drugs marketed
between 1938 and 1962. They found that only 45 of some 1,200 fixed dose
combination drugs were rated as effective. The American Council on Drugs, in
early 1970s, stated that “combination or mixtures containing two or more
active ingredients in fixed ratio are, in most instances, not recommended.”
Despite
acknowledging the therapeutic advantage of the “combinations of drugs” and
their additive or synergistic effects as beneficial, the 12th
edition of The Pharmacological Basis of Therapeutics noted: “There are many
examples of pharmacodynamic interactions that can produce significant adverse
effects.” Such strong policy statement, mentioned in the ‘bible’ of
pharmacology, perhaps, clarifies the physician’s dilemma whether to prescribe
or not to prescribe FDCs.
WHO
recommendations
A World
Health Organisation Expert Committee on the Selection of Essential Drugs met in
Geneva from 17 to 21 October, 1977 and laid down the guidelines for establishing a list of essential drugs.
There, the WHO recommended that fixed-ratio combinations are only acceptable if
the following criteria are met: (i) clinical documentation
justifies the concomitant use of more than one drug; (ii) the therapeutic
effect is greater than the sum of the effect of each; (iii) the cost of the
combination product is less than the sum of the individual products; (iv)
compliance is improved; (v) sufficient drug ratios are provided to allow dosage
adjustments satisfactory for the majority of the population. Thus, WHO listed
250 essential drugs and there were only 7 combination drugs in that.
Subsequently, the policy of WHO towards FDC undergone a major shift.
In 2005, while fixing its guidelines for registration of fixed-dose combination,
the WHO suggested that the development of FDCs was becoming increasingly
important from a public health perspective; particularly in the management of
human immune-deficiency virus/acquired immune-deficiency syndrome (HIV/AIDS),
malaria and tuberculosis which were considered to be the foremost infectious
disease threats.
But, in the same report, the WHO also noted: FDCs
have advantages when there is an identifiable patient population for whom
treatment with a particular combination of actives in a fixed ratio of doses
has been shown to be safe and effective, and when all of the actives contribute
to the overall therapeutic effect. Additionally, there should be real
clinical benefits in the form of increased efficacy; a reduced incidence of
adverse effects; lesser cost than that of separate products given concurrently
and all such claims should be supported by evidence. Therefore, the model list
of 312 essential drugs, prepared by the WHO in March 2005, includes only 18 FDCs.
The Indian perspective
Unfortunately, many FDCs being introduced in India are
usually irrational. The most pressing concern with irrational FDCs is that they
expose patients to unnecessary risk of adverse drug reactions. For example, a
variety of NSAID combinations available for sales (often as over the counter
products) might not be needed at all. The ‘combined’ pills are marketed with
slogans like ‘ibuprofen for pain and paracetamol for fever’ and ‘ibuprofen
for peripheral action and paracetamol for central action’. There is no
synergism when two drugs, acting on the same enzyme, are combined. But, such
gimmicks burden the patients with extra cost and extra adverse effects.
To assess the rationality of FDCs enlisted in the
Central Drug Standard Control Organization’s (CDSCO) list, a study was
conducted on 264 FDCs which were marketed in India during 2009 to 2014. Rationality
analysis was done as per the WHO guidelines. Maximum combinations were from
cardiovascular system followed by the combinations from pain/musculoskeletal,
anti-infective, endocrine, central nervous system (CNS) and respiratory system.
According to rationality scoring scale, 51.89% FDCs were found to be irrational;
28.40% semi-rational and only 19.69% were rational. Moreover, 56.81% FDCs were
adding up adverse drug reactions while 46.59% FDCs had chances of increased
adverse drug reactions due to their active pharmacological ingredients.
The ban and the lapses of the government
Since it is unethical to expose the patients to
medicines with unproven efficacy, safety, suitability, rationality and cost
benefit; the Ministry of Health and Family Welfare (MHFW) of the government of
India, through a gazette notification on March 15, 2016 declared ban of 344
FDCs from the market with immediate effect. But, the moot point
remained whether these measures were sufficient? Over the years, the Indian
Drug Control Authority have been issuing notifications to ban many FDCs like
analgin + pitofenone; vitamins B1 + B6 + B12; cyproheptadine + lysine; etc. Incidentally,
the manufacturers never stopped from coming out with newer irrational FDCs.
It is interesting to note that, on July 12, 2018, the
CDSCO published a list of FDCs and permitted their continued manufacturing and
marketing of which many FDCs were neither in the essential list of WHO nor mentioned
in any standard text or reference books; reputed medical journals. For
instance, fixed dose combination of Nimesulide + Paracetamol: Nimesulide alone
is more antipyretic than paracetamol, more anti-inflammatory than aspirin, and
equivalent in analgesia to any of the NSAIDS alone. Therefore, the addition of
paracetamol is unlikely to gain efficacy. Though, there are possibilities of increased
hepatotoxic effects from the combination. Another example is ciprofloxacin +
tinidazole. Becaues of such FDCs of quinolones and nitroimidazoles, the patient
is exposed to greater risk of gastrointestinal (GI) irritation and serious
bleeding from unsuspected peptic ulceration. Thus, the technical expertise of
CDSCO itself is questionable. And, if the government authorities are deficient
in technicalities, then how can they ensure health safety and cost effective
medications for the general population?
National List of Essential Medicines (NLEM)
The purpose of NLEM is to promote rational use of
medicines considering the three important aspects - cost, efficacy and safety. It
is the key instrument in balanced healthcare delivery systems which includes
accessible, affordable and quality medicines at all the primary, secondary and
tertiary levels of healthcare. The WHO introduced the concept first in 1977
which has successively been adopted by many countries.
But, in India, efforts were made much earlier to
prepare an essential drug list with the main objective of price control.
Accordingly, in 1967, the Committee on Essential Drugs Tariff Commission
prepared a list of 17 essential drugs. In 1968, it studied the cost structure
of those 17 essential bulk drugs and their formulations; with an aim to bring
down their prices. Drug Policy 1978 prepared a list of 37 ‘highly essential and
life saving’ bulk drugs.
Priorities for preparing an essential drug list have
always been misplaced in India. Hathi Committee’s recommendations in 1975 were
to prepare an essential list of 104 bulk drugs. Later, essential drug list was
replaced by a ‘priority list’ of 95 drugs. It was a major shift in 1996 when
the MHFW prepared and released the first National List of Essential Medicines
of India consisting of 279 medicines. Thus, the ‘essential drugs’ was
derogatorily reduced to ‘essential medicines’.
Subsequently, the list was revised in 2003 and had 354 medicines. Later
in 2011, the list was revised and had 348 medicines. NLEM 2015 was
prepared with 376 medicines after adding a total of 106 medicines and deleting 70
medicines from 2011 list. Till June 2018, NLEM had 851 medicines including
4 medical devices e.g. cardiac stents, drug eluting stents, condoms and intra
uterine devices.
Misconceived notion: Distorted objective
Pharmaceuticals do have congruity with the overall
healthcare system. And, the healthcare system is necessarily guided by the
health policy and the drug policy. A comprehensive health policy and a people
oriented drug policy depend upon the ideas and ideologies of the ruling
dispensation. In absence of pro-people socio-economic policy, there can never
be a discipline in pharmaceuticals.
In the sphere of drug production, marketing and
distribution; there is an utter chaos in India. As per available information, Indian
pharmaceutical market does have 3062 generic and 110,355 branded
generic medicines that have listed their prices. While medicines are essential
tool for healthcare management, but due to policy deficiencies of the
government they have become just profiteering machines for the drug cartel.
This has led to the problem of inadequate supply of essential drugs and,
simultaneously, there has always been a proliferation of non-essential,
hazardous and irrational pharmaceutical products.
Worldwide and in India;
numerous studies, reports and articles have been published on this issue, even
then the same could not be contained due to lacunae in subsequent drug
policies. Therefore, the government’s own agencies
find it difficult for themselves and become defenseless when challenged in the
court of law. Without bringing stringent and pro-people legislative changes,
preparing a list of banned drugs is too meager an act in the part of the
government of India.
History of ineffective firefighting
Facing wrath inside and outside the Parliament, the
government of India, for the first time in 1982, decided to ban the production
and sales of certain drugs. The Drug Technical Advisory Board (DTAB)
recommended the ban of 18 FDCs and, accordingly, the Drug Controller (India)
issued notification banning their manufacture from September 30, 1982 and sales
from April 1, 1983. The Bombay High Court stayed the order of the Drug
Controller (India) on application of Retail and Dispensing Chemist Association
of Bombay. The court ordered that a gazette notification should be published
with a list of formulations under Section 26 (A) of the Drugs and Cosmetic Act.
But, the Drug Controller could not give effect to this notification since
Boehringer Knoll, a pharmaceutical major, challenged the government’s order in
the Bombay High Court and got an interim stay.
Similarly, the Drug Controller’s notice of banning the
production of Oestrogen-Progesterone combination drugs on June 13, 1982, was
challenged in the Bombay and Calcutta High Courts by the pharmaceutical
companies namely Ciba-Geigy and Unichem and stay orders were obtained. The
MHFW, on July 23, 1983, issued notification for banning 25 FDCs. Due to High
Courts’ orders and certain legal lacunae, the government could not implement
its own decision and, as a result, the banned drugs were continuously
manufactured and sold in the country.
After 33 years, the government of
India could experience the same fate, as it had banned 344 FDCs in March 2016,
with subsequent five additions to the list; following a report submitted by the
Kokate Committee. Immediately, the drug makers including Pfizer, Procter &
Gamble, Abbott, Glenmark, Sanofi, Wockhardt, Cipla, Lupin and Dr Reddy's had
moved various courts against the decision. The Delhi High Court alone had
received over 450 petitions seeking a stay on the ban. In December 2016, the
Delhi High Court quashed the Centre's decision. This time the court noted that
the government had acted on the advice of a 'technical committee', instead of
consulting the DTAB which was a violation of the provisions of the Drugs and
Cosmetics Act.
In December, 2017, the health ministry
challenged this ruling in the Supreme Court and the apex court directed DTAB to decide the fate of the
FDCs. The Court,
however, freed 15 of 344 FDCs and ordered the government not to use the DTAB
report to prohibit them
since they have been manufactured in India since before 1988.
This exception covers several popular cough syrups, painkillers and cold
medication with annual turnover of more than Rs 740 crore.
In September, 2018, though
the DTAB recommended the
banning of 328 FDCs, the government is still struggling in the court of law which
suggests that there hasn’t been much change in the country’s pharmaceutical
scenario for over three decades. Ironically, the government is yet to suggest
any legislation by which it can take effective steps to implement its own
decisions leaving aside its duty to protect the ailing people from the
hazardous effects of irrational FDCs.
Tasks
ahead
India, with such well off
pharmaceutical industry and a large number of trained medical personnel, should
be in a position to provide its people with adequate and advanced healthcare
facilities including the modern medicines which should be simultaneously
rational and affordable. For this, the government should develop people’s
oriented national policies, long term strategies and effective action plan.
Considering these, we may suggest few tasks:
i.
The
government at the centre should immediately form a high power Committee with
representation from the Ministries of Finance; Health and Family Welfare;
AYUSH; Chemicals and Fertilizers; Petroleum and Natural Gas; Commerce and
Industry; Corporate Affairs; Human Resource Development; Law and Justice;
Statistics and Programme Implementation; Women and Child Development and Human
Resource Development.
ii. That
Committee should interact with all stake holders including doctors; scientists;
academic experts; health activists; lawyers; industry representatives;
dispensing chemists; trade union functionaries and common people to the extent
possible, seeking suggestions from all.
iii.
Based
on those suggestions, the government should formulate a comprehensive health
policy aiming to provide with primary, secondary and tertiary healthcare
services to all.
iv.
In
congruence with such universal health policy, a list of essential drugs should
be prepared; considering the demographic divergence of India and following the
WHO list of essential drugs. No drug outside that list should be allowed to
manufacture, marketing or sale in India.
v.
Such
national list of essential drugs should determine the national pharmaceutical
policy. The robust pharmaceutical industry of India should follow the ethical
way of marketing and selling medicines which should be made mandatory. No
deviation should be allowed in any manner whatsoever. The pharmaceutical
industry must be guided by the government’s comprehensive healthcare plan and
the healthcare need of the people.
vi.
Stringent
methodologies should be developed for any kind of drug trial. The Patent Act
should also be tightened enough to protect the self-reliance of the drug
industry.
vii.
Legal
provisions are to be made in such a manner so that the violators should face
exemplary punishment through trial in the court of law.
Conclusion:
To accomplish the above tasks, it is
necessary that the government exercises its political will. The government at
the centre should aim high to rescue its people from the menace of hazardous
medicines. However, any pro-people policy is always developed through people’s
movement. Hence, an active participation of people across all walks of life is
the need of the hour to turn the government’s policies in their favour. In this
case, by all means, we have to fix the combination drugs in their right dose.
2. Complete list of 344 drugs banned
by the Ministry of Health Family welfare;
National Health Portal
3. FDCs permitted for
continued manufacturing and marketing; CDSCO
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