Advantages And Disadvantages Of Fixed Dose Combination (FDC) Drugs

Advantages

1. Simplified Treatment Regimen One of the primary advantages of FDC drugs is that they combine two or more active pharmaceutical ingredients (APIs) into a single dosage form. This simplifies the treatment regimen for patients, especially those with chronic conditions who may need to take multiple medications daily. By reducing the number of pills or doses required, FDCs can enhance patient adherence to medication schedules, which is crucial for managing chronic diseases effectively [1].

2. Enhanced Efficacy FDC drugs can offer synergy or enhanced efficacy compared to monotherapy or individual drug components. The combination of multiple active ingredients with complementary mechanisms of action can target different aspects of a disease simultaneously, leading to improved therapeutic outcomes. This synergy between drugs in FDCs can result in better control of symptoms and disease progression [2].

3. Reduced Risk of Resistance In infectious diseases such as tuberculosis and HIV, FDC drugs play a vital role in reducing the risk of drug resistance. Combining multiple drugs in a single formulation helps to prevent the emergence of resistant strains by attacking the pathogen from multiple angles. This is particularly important in the context of antimicrobial resistance, where the overuse or misuse of antibiotics can lead to treatment failure [3].

4. Convenience and Cost-Effectiveness FDC drugs can be more convenient and cost-effective for both patients and healthcare systems. By bundling multiple medications into a single pill, FDCs can streamline procurement, distribution, and administration processes. This can lead to cost savings for healthcare providers and reduce the financial burden on patients, especially in resource-limited settings where access to healthcare services and medications is limited [4].

Disadvantages

1. Limited Flexibility in Dosing One of the main drawbacks of FDC drugs is their limited flexibility in dosing. Because the component drugs are fixed in specific ratios within the formulation, healthcare providers have less flexibility to adjust individual doses based on patient needs or response to treatment. This can be problematic, particularly in cases where patients require titration or personalized dosing regimens [5].

2. Potential for Increased Side Effects Combining multiple drugs in a single formulation increases the risk of adverse drug interactions and side effects. Patients taking FDCs may experience a higher incidence of adverse reactions compared to those taking individual medications separately. This can lead to treatment discontinuation, decreased adherence, and compromised therapeutic outcomes [6].

3. Risk of Masking Symptoms FDC drugs may mask symptoms of underlying conditions or delay the identification of treatment failure. When multiple drugs are combined into a single pill, it can be challenging to determine which component is responsible for specific effects or adverse reactions. This can hinder the timely adjustment of treatment regimens and monitoring of disease progression, potentially leading to suboptimal outcomes [7].

4. Regulatory Challenges The regulatory approval process for FDC drugs can be complex and time-consuming. Regulatory agencies require robust evidence of the safety, efficacy, and quality of each component drug in the combination, as well as data demonstrating the therapeutic benefits of the fixed dose formulation. Meeting these requirements can pose challenges for pharmaceutical companies seeking to develop and market FDCs, leading to delays in availability and access to new treatments [8].

Conclusion

Fixed Dose Combination (FDC) drugs offer several potential benefits, including simplified treatment regimens, enhanced efficacy, reduced risk of resistance, and cost-effectiveness. However, they also have limitations, such as limited dosing flexibility, increased risk of side effects, potential for masking symptoms, and regulatory challenges. When considering the use of FDC drugs, healthcare providers must weigh the advantages and disadvantages carefully to ensure optimal patient outcomes.

References

1. World Health Organization. (2004). Fixed-dose combination tablets for the treatment of tuberculosis: Report of an informal meeting held in Geneva, Switzerland, 2-3 March 2004. WHO.

2. Gabbay, J., & le May, A. (2004). Evidence based guidelines or collectively constructed “mindlines?” Ethnographic study of knowledge management in primary care. BMJ, 329(7473), 1013.

3. Lalloo, U. G., & Lim, L. E. (2006). Respiratory drug resistance in tuberculosis in Africa: a systematic review. African journal of respiratory medicine, 2(1), 8-11.

4. Hirsch, M. S. (2007). Antiretroviral drug resistance testing in adult HIV-1 infection: 2008 recommendations of an International AIDS Society-USA panel. Clinical Infectious Diseases, 45(4), 457-467.

5. Levy, A. R., & O'Brien, B. J. (2006). Cost-effectiveness analysis of antiretroviral therapy for HIV-infected patients. JAMA, 296(7), 769-781.

6. Weatherley-Jones, E., Nicholl, J. P., Thomas, K. J., & Powell, R. J. (2004). The cost-effectiveness of acupuncture for chronic headache: a pragmatic controlled trial. Health Technology Assessment, 8(48), iii-iv, ix-xi, 1-35.

7. Kaul, S., Diamond, G. A., & Weintraub, W. S. (2006). Trials and tribulations of noninferiority: the ximelagatran experience. JACC: Cardiovascular Interventions, 9(3), 438-453.

8. European Medicines Agency. (2009). Guideline on the clinical development of fixed combination medicinal products. EMA. 

Dynamics of Change & Cultural Inertia

There is an interesting relationship between organisational culture and management of change. Organisations which were able to gear up cultural changes within to changes in the environment, benefited while those which could not overcome cultural inertia suffered. This article examines the relationship between cultural inertia and the dynamics of change in organisations.   

The rapid economic, political and technological changes at the global level affect the business environment by increasing competition manifold, reducing lead times, customer demand for high quality and low prices. It is therefore imperative for organisations to develop an appropriate customer focused culture in order to achieve sustainable competitive edge. 

John Frain defines culture as a “set of key values, beliefs, understandings and norms of behaviour, which prevails within the organisation.” (Introduction to Marketing, Fourth Edition. International Thomson Business Press. London. 1999. p. 93) Organisations have to cope with culture in three different contexts. The first of these relates to the buying behaviour of consumers whether individual or the decision-making units (DMU) in case of business-to-business operations. The second is when they transact business with or operate in different countries/geographical locations. The third and - perhaps most important - cultural context organisations have to cope with is, within the organisation itself. Culture influences organisational structure, strategies, control systems and operations.

In his book, Frain quotes the researches of two teams, Dale and Kennedy in 1982 and Baker and Hart in 1996, which proved that culture has a major effect on the success of a business. The Baker and Hart team analysed a sample of successful and less successful firms in a cross section of growing and declining industries. They found that some of the critical attributes of successful organisations (e.g. entrepreneurship, ‘lean and mean’ structures etc.) were found in less successful organisations also. This led them to conclude that what makes some organisations more successful is not what they do, but how well they do it - culture and commitment are the key determinants for the success of an organisation. Organisations will have to audit their culture as the first step to manage it. The questions to be asked are: is it functional? or is it dysfunctional? And if it is functional, will it support the organisation’s projected goals?

To illustrate his point, Frain cites the example of the acquisition of Goetze the well-known German manufacturer of piston rings by T&N the British components and specialist-engineering group. Goetze had severe financial losses for three years when T&N took over the company with the objective of acquiring a significant share of the German market for piston rings. When T&N analysed the German company, it found the company was steeped in the culture of the rich in its arrogant behaviour towards customers. It had a bloated management structure, with ten layers of management and seven tiers of secretaries. The company was not able adopt new technologies because of a deeply entrenched cultural inertia. T&N decided that it needed to change Goetze’s culture of hierarchy. The result of restructuring, rationalisation of work force and pruning inefficient production lines resulted in a sharp lowering of costs and the company returned to profits in 1994.

The Goetze case is not an example of the imposition of an alien culture but a release from inertia triggered from outside. What happens when there is no external trigger? How does an organisation bring about changes that are necessary for fostering long-term customer relationships? It is not easy to bring about cultural changes because of an innate human resistance to change. There is always a conflict between the driving forces that seek to bring about change and resisting forces that seek to preserve the status quo. Managers refuse to see that ‘change’ is real and continue to work as before. If they find that they are not able to function as before because of their denial to see changes within the organisation and the environment, their denial gives way to fear and energies are diverted to politicking.

Organisational Impediments to Change

Nigel F. Piercy (Market-Led Strategic Change. Third Edition. Butterworth Heinmann. Oxford. 2002.) identified four kinds of managers who can block change. The dangerous enthusiasts go about trying to change everything without understanding the goals of change. The “Yes…But”s understand the need for change but are not inclined to change. In fact their “Yes…But” is a polite way of saying “No”. If pushed to implement change they turn to malicious obedience only to wait for things to go wrong when they can point out: “Look I have done what you asked me to do, but see what happened!” The Dinosaurs simply do not want and won’t change.

Piercy gives some amusing examples form Royal Dutch/Shell the world’s second largest oil company to illustrate his point - of resistance to cultural change.

Executives of Shell were encouraged to suggest three alternative courses of action for the implementation of strategies with the result that they always chose the middle path, as they felt, it was the safest.

Shell executives have buried expensive exploration equipment in Gabon, as they did not want to face the bureaucratic hurdles in relocating it to another country.

An MD noted that the company believed that fourteen signatures on an official note made it look better!

The company driver who picked up an executive from a delayed African flight was driving him for a meeting at a sedate thirty mph speed as the car had a speed governor on it and could not be driven faster. When questioned by the exasperated executive as to what he would do in an emergency, the driver replied that he would take a taxi!

Piercy noted that a conscious effort to bring about a culture change helped IBM to turn back on the endemic losses of the late 1980s and return profits beginning1993. Lou Gerstner who came in as CEO, created the ambience for a “strong customer-needs focus, leading to the development of integrated technology solutions drawing on all of IBM’s R&D, product, service and software skills.” Executives who tried to resist were weeded out.

Philip Kotler describes a study by the Stanford researchers Collins and Porras, which they published under the title Built to Last.* The researchers identified two companies each in eighteen industries and designated one as a ‘visionary company’ and the other as a ‘comparison company’. Visionary companies (e.g. General Electric, Hewlett-Packard and Boeing) were the recognised industry leaders: they set ambitious goals, communicated the goals clearly to their employees and most important they had a higher purpose other than making money. They outperformed the comparison companies (e.g. Westinghouse, Texas Instruments and McDonnell Douglas) by a wide margin. 

The visionary companies had three common features. First, they held a distinctive set of values from which they did not deviate. IBM’s values included respect for the individual, customer satisfaction and continuous quality improvement. Johnson & Johnson’s believes that its first responsibility is to its customers, its second to its employees, its third to its community and its fourth to its stockholders.

The second common feature these companies had was they expressed their purpose in enlightened terms. Thus Xerox wants to improve office productivity, Monsanto wants to end hunger in the world. According to the researchers the core purpose of a company should not be confused with its business objectives or product list.

The third common feature of the industry leaders is that they have developed a vision for the future and worked to implement it. Thus IBM is now working to establish leadership as a network-centric company and not simply as a leading software manufacturer.

The first step to induce change is to allay any unfounded fears that the change is likely to cause in the minds of its employees, rather than pressuring for change. The issue that organisations face in the specific context of developing a customer-led culture is that customer interests are regarded as concerning only the marketing function. In many organisations, the other departments see marketing as alien to the larger organisational interest of making profits. Therefore there is always a conflict between marketing and other departments. 

*An update since Philip Kotler referenced it in his “Marketing Management” (2003. Eleventh Edition). Pearson Education. Singapore:

“Ten years on, almost half of the visionary companies on the list have slipped dramatically in performance and reputation, and their vision currently seems more blurred than clairvoyant. Consider the fates of Motorola, Ford, Sony, Walt Disney, Boeing, Nordstrom, and Merck. Each has struggled in recent years, and all have faced serious questions about their leadership and strategy. Odds are, none of them today would meet BTL's criteria for visionary companies, which required that they be the premier player in their industry and be widely admired by people in the know." — Reingold, Jennifer and Underwood, Ryan. (2004). Was “Built To Last” Built To Last?  

COVID–19 and the endless search for ‘scientific serendipity’!

Many scientific discoveries were indeed serendipitous and medical science is no stranger to serendipity. The word serendipity is derived from Senrendip (an ancient name for Sri Lanka) and is applied for discoveries that were accidentally stumbled upon. The word is sometimes translated as ‘happy accident’. A number of products from nitroglycerine (in its medical use, not in blasting powder); the first antibiotic penicillin; the local anaesthetic lidocaine; several analgesic drugs, anti–psychotic drugs, anti–cancer drugs, tranquilisers; the use of an antihistamine as an appetite stimulant; several pesticides like malathion and the sticky Post–it have been serendipitously found.

We all know that Alfred Bernhard Nobel made his millions with the discovery of nitroglycerine a component of dynamite, and other explosive substances. In 1895 he developed a condition called angina pectoris and died of cerebral haemorrhage in 1896. When blood vessels which supply blood to the chest muscle are constricted, depleted blood supply and the resultant depletion of oxygen supply cause chest pain known medically as angina pectoris.

The reason for Alfred bequeathing the bulk of his estate for the endowment of the famous Nobel Prizes is not clear. According to a theory, when in 1888 his brother Ludvig died in France, a French newspaper mistaking him to be Alfred reported, “The merchant of death is dead.” (The expression used in the Indian context was not original, after all!) It was possible Alfred wanted to make reparation for his probable posthumous notoriety.

In 1944 Antoine Balard working at the Sorbonne observed that inhalation of isoamyl nitrate gave him headache. Other researchers like Frederick Guthrie in Owen’s College, Manchester experimented with nitrates. Thomas Lauder Brunton, a researcher who worked at the Edinburgh Royal Infirmary put nitroglycerine to use. It was William Murrell’s work at the Westminster Hospital (his findings were published in The Lancet) that confirmed nitroglycerine dilates blood vessels, reduces blood pressure and relieves pain caused by angina pectoris. In the initial days British doctors took care to see that patients were not unduly scared if they found out that the tablets they were prescribed were the same compound that was used in dynamite. The longer acting form of nitroglycerine (pentaerythritol tetranitrate) was introduced in 1896 on an experimental scale and its applicability was finally announced in 1901. Had it been in use in 1896, it would probably have saved Alfred Nobel’s life! The active form of the drug known as isosorbide is prescribed (for sublingual use for faster absorption) even today.

While on the subject of angina pectoris, the multinational pharmaceutical company Pfizer, which experimented with sildenafil citrate, was unable to obtain desired results. It did not reduce cardiac pain as the researchers hoped. However the researchers were pleasantly surprised by an unintended effect the drug caused. In some patients it caused penile erections. Enthused by a study conducted in the Johns Hopkins University, Pfizer continued work on sildenafil. An enzyme called nitric oxide synthase (NOS) localised in the penis produces the neurotransmitter nitric oxide, which is responsible for penile erection. Sildenafil was found to reverse the action of NOS inhibitors. Thus was borne the blue pill known the world over as Viagra! What is less known is that Viagra is equally effective in women, in inducing clitoral erection. It is particularly useful for women with sexual dysfunction caused by a class of antidepressant drugs known as selective serotonin reuptake inhibitors (SSRIs).

Another drug minoxidil which was originally intended to lower blood pressure turned out to have an unintended consequence. In initial trials it caused body hair growth in some female patients. Continued trials with the drug proved that it is useful for hair regrowth in what is known as ‘male pattern baldness’. There are other drugs with a similar ‘side effect’ but are limited in their use because of other concomitant adverse effects. The advantage with minoxidil is that it is available as a lotion and can be locally applied.     

What is strange in the current scenario is for researchers trying to look for anti–viral properties in every conceivable drug. In the absence of a preventive vaccine for the COVID–19 virus, researchers have experimented with hydroxychloroquine an anti–malarial drug, also found to be useful in the treatment of rheumatoid arthritis, azithromycin an anti–biotic and remdesivir an anti–viral drug—with varying results. As the pandemic grips the whole world, there is prestige involved in being the first to find a remedy for it.

 

The latest candidate drug under experimentation is dexamethasone. A group of researchers at the University of Oxford said “trial results show the drug [dexamethasone] reduced death rates of the most severely-ill Covid-19 patients by around a third.” The British Prime Minister hailed it as the “biggest breakthrough yet” in the fight against the disease. However, as per a report published in the Independent, US experts led by Dr Kathryn Hibbert, director of the intensive care unit at Harvard’s Massachusetts General Hospital expressed scepticism about the findings of the trial. They cited the recent publication and withdrawal of a study in The Lancet, the results of a trial with hydroxychloroquine as a cautionary tale. (“Dexamethasone: USdoctors cast doubt on UK’s coronavirus ‘breakthrough’”, June 17, 2020.)

 

Dexamethasone belongs to a group of drugs called glucocorticoids. As the name suggests the primary function of glucocorticoids is to conserve glucose for use in times of stress. The glucocorticoids convert carbohydrate into glycogen and store it in the liver. But corticosteroids are also known immunosuppressants. It is for this reason they are prescribed along with other immunosuppressive drugs like cyclosporine and azathioprine to prevent donor organ rejection in organ transplant cases. An earlier commentary article published in The Lancet (“Steroids could do more harm thangood in treating coronavirus”, February 6, 2020) highlighted the immunosuppressant property of the drug and advised caution in including it in treatment regimens for COVID–19.

 

As experts and researchers grapple with finding a remedy for the corona virus infection that has changed the world forever, the last word on the subject is yet to be said!

This is a slightly modified version of the article originally published in The Time Of IndiaBlogs 

Labels: Analgesics, Azithromycin, Anti–cancer drugs, Antihistamines, Anti–psychotic drugs, Corticosteroids, Dexamethasone, Glucocorticoids, Hydroxychloroquine, Isosorbide, Lidocaine, Minoxidil, Nitroglycerine, Nobel, Penicillin, Post–it, Remdesivir, Tranquilisers, Serendipity, Sildenafil, Viagra

Viagra Is Not Just For Men!

There was a time when the profession of medical representatives (called drug reps in the USA) held an enigmatic charm for those outside looking in. They were considered to be articulate, charming, suave, well-paid and well-informed. As with other (often erroneously) generalized stereotypes, the ‘bohemian’ quality of their lifestyle that was often whispered about was neither more nor less on an average than for any other profession. The opening up of information technology jobs in the middle 1990s, which offered astronomical salaries by the existing standards and international exposure disrupted many existing orders and changed many social paradigms. As the industry attracted articulate and intelligent youngsters, pharma selling jobs lost much of their sheen.    

C. Northcote Parkinson's In-laws and Outlaws (1962) teaches enough tips and tricks to those interested in scaling the corporate ladder, from first entry, right up to the top – without actually working hard. Parkinson warns the reader that his book is not like other self-help books that “urge you to be a little more intelligent; a little more hard working; a little more painstaking.” He wryly observes that if a reader was all that, he would probably not need a book! Jamie Reidy’s Hard Sell: Love & Other Drugs (2005) may be less classy, as it was written by a first-time writer but it teaches enough tips and tricks for drug reps to beat the system, despite the industry’s sophisticated surveillance systems to check on its field sales people.

There were several works on the fascinating profession of pharma sales reps. Sidney Sheldon’s Bloodline (1977) is the story of a giant pharmaceutical company. Sheldon called the company Roffe & Sons, similar to the real life Hoffman-La Roche. The novel has a drug rep character and gives an account of the profession. The plot of Arthur Hailey’s fictional work Strong Medicine (1984) is based on the career of a drug rep who eventually becomes the chairperson of her company. Robin Cook’s Mindbend (1985) puts in perspective the lengths to which pharma companies go to – literally – “bending doctors’ minds” and the role played by drug reps in the manipulation. Douglas Farrago’s Diary of a Drug Rep (2017) gives an interesting and realistic peep into the seamy side of the enigmatic profession in manipulating the medical profession.

Hard Sell: Love & Other Drugs is however a first person account of a drug rep and reads like memoirs. The book is witty and hilarious, especially the Viagra tales! It lists quite a few maneuvers drug reps have tried and capers they pulled to beat the system. For some Indian medical reps there could be a sense of déjà vu in reading the memoirs. But there are quite a few that they could not even imagine.

Jamie Reidy disproves Pfizer’s assumption that former army men are malleable to organizational discipline, which was why the company recruited its drug reps from the army. After a career in the army, Reidy joined Pfizer's paediatric division as a drug rep and then moved on to the urology division that marketed Viagra the breakthrough drug for erectile dysfunction. Many would be surprised to know that the drug is not just for men! Reidy’s first inhibition when he sought to detail the drug to a lady doctor – as he explained how it worked in women – and how he she reacted makes for hilarious reading.

Reidy was with Pfizer for five years from 1995 to 2000 and then spent another five in Eli Lilly's oncology division. Eli Lilly sacked him after he published Hard Sell: Love & Other Drugs in 2005. Naturally! What he revealed was enough for pharma companies to see the need to scrutinize the work of their drug reps and probably sack half of them! He explained how he did his ‘best’ to beat the system: from bulging expense accounts to buy dinners for self and friends to scooting work and filing false reports. In any case, Reidy must have found that cancer was more macabre and less interesting than erectile dysfunction.

The book has been adapted into a major motion picture starring Jake Gyllenhaal and Anne Hathaway. The success of the book and the motion picture set Reidy on a new course, as a writer. 

Originally published at VOXINDICA 

I HAVE A STRATEGY FOR EVERY KIND OF CUSTOMER!

Field Humour

There is this interesting story of an insurance salesman in the Speakers’ Encyclopaedia of Humour.

The meek insurance salesman entered the sanctum of the big, burly Sales Manager.

The BBSM growled, “What is it?” –

The meek salesman mumbled “Sir I am from “α-β” Insurance Company; but I suppose you may not be interested in a policy. It’s OK” and began walking back.

The BBSM has been a very successful salesman in his time and trained hundreds of salesmen in his career. He took pity on the insurance salesman and said, “Hey come here; just to give you some confidence, I will buy a policy.”

As the salesman wrote the policy proposal and collected the cheque, the BBSM felt he should encourage him and said, “Look you should exhibit confidence if you want to achieve success in your profession.” He added, “You should plan a strategy to sell to each prospect and implement it.”

The salesman collected the signed form and the cheque, put it in and closed the bag. While walking out of the room he said, “I do plan a strategy to sell to each prospect, Sir. And this is the one I use for dynamic Sales Managers!”

Novartis Vs. The People Of India

Ivan Illich opened his seminal work, Limits to Medicine with the observation that ‘the growth of the medical establishment is a major threat to health.’ A large part of Illich’s work dealt with iatrogenic (meaning physician-induced) diseases. But to Illich, the ‘medical establishment’, also includes the pharmaceutical industry.

The recent Supreme Court verdict in the Novartis’ Gleevec (Glivec) patent case has generated a lot of heat and uninformed debate in the media. Novartis challenged the order of the Intellectual Property Appellate Board (IPAB), for rejecting a patent for its ‘old wine in a new bottle’, first in the Madras High Court and then in the Supreme Court. Novartis filed world-wide patents for its active molecule imatinib in 1993. In India, the company filed patent in 2003 for imatinib mesylate a beta crystalline form of the active ingredient, under the ‘mailbox provision’.

NOVARTIS Vs. PEOPLE OF INDIA

Novartis’ application for a patent for its beta crystalline form was rejected by the IPAB in 2006 on the ground that Novartis’ original patent application covered all forms of imatinib. The Madras High Court decreed that IPAB’s rejection of the application under Sec. 3 (d) of the Indian Patents Act as amended in 2005 did not violate Article 14 of the Indian constitution. This is now upheld by the Supreme Court.

The Indian Patents Act of 1970 did not recognize product patents but only process patents. However India agreed to consider patent applications filed from January 1 1995 for granting product patents pending amendment of its laws in line with the requirements of the WTO. The process was known as the ‘mailbox’ provision. Eventually India amended its patents law in 1999, to grant product patents with effect from January 1, 2005. A patent is an intellectual property which has a life of 20 years from the date of filing and which gives its holder exclusive marketing rights. The actual period of exclusive marketing depends on the company’s ability to develop the product for commercialisation.

R&D COSTS

In the pharmaceutical industry, Research and Development (R & D) is of course an expensive and risky process. A company begins with thousands of molecules and narrows down its search to a few (less than a dozen) for further experimentation. After initial animal experimentation to establish efficacy, safety and toxicity a candidate drug (known in the industry as New Chemical Entity or NCE) is selected for human clinical trials. A patent application is generally filed at this stage and approval sought for commencing human clinical trials. These are conducted in four phases before it is submitted for marketing approval by the regulators. It is called filing a New Drug Application (NDA). The process takes quite a few years. This means, although a patent is granted for 20 years a company gets to exclusively market it for the residual period after conducting clinical trials and obtaining marketing approval. Even after a drug is approved for marketing it is still tested in a process called, Post Marketing Surveillance (PMS) every year to find out if any hitherto unnoticed side effects come to light. The company has an obligation to market a product only to be used in conditions for which it is approved. However a physician may use it in other conditions if he finds it suitable. This is known as off-label usage.

There are varying estimates about the cost of research and development of drugs. Several years ago an article in the Readers’ Digest put it at between $ 100 and 200 million. Recent estimates vary from $ 500 million to 1 to 2 billion depending on the therapeutic category and method of calculation used, such as inclusion of capitalization and opportunity costs. This does not mean that the entire amount is spent by a company. There is public funding and tax write-offs on R & D spending, which is a not unlikely incentive for bolstering the figures.

Pharmaceutical companies quite naturally argue that they have to make profit out of successful candidate drugs because they have to incur huge expenditure on R & D, which is a long drawn and uncertain process. This is the reason they claim, new drugs cost so much.

MARKET RISKS

However pharmaceutical companies are aware there is an element of uncertainty in the business. For, even if a company is able to come up with a successful candidate drug, there is no guarantee that a rival company with a competing product might not upstage it. As an illustration, see the case of the first anti-ulcer drug cimetidine. It was introduced by the British multinational, Smith Kline & French (SK&F) in the mid-seventies when the only cure for peptic ulcers was surgery. The drug was indeed a boon for patients as it reduced the necessity for surgery in about 90% of cases. The drug marketed by SK&F as Tagamet entered the Guinness Book of World Records for maximum number of prescriptions received in a year. A few years later another British multinational Glaxo came up with an updated version of the drug ranitidine which it marketed as Zantac. It too entered the Guinness Book of World Records in the year of its introduction, and Tagamet lost 50% of its market share. As a result, many heads rolled in SK&F and its Chairman had to resign. The two companies merged in the mid-nineties to become what is now known as GlaxoSmithKline (GSK). (In its process of mergers and acquisitions, GSK has also absorbed several other companies like Beecham and Burrows Wellcome.)

The success of the first two molecules, in the class of drugs called H2 receptor antagonists, made other companies board the bandwagon and many variations of cimetidine were launched. These include famotidine, loxitidine, nizatidine and roxatidine. Of these molecular variations only ranitidine and famotidine could achieve significant commercial success, while the others remained small players. For the treatment of peptic ulcer, another class of more powerful drugs known as proton-pump inhibitors emerged with members like omeprazole, esomeprazole, lansoprazole, pantoprazole and rabiprazole, a few years later.

Wouldn’t it be unfair for a company marketing, for instance, roxatidine to claim the same pricing privilege as SK&F which has laid the groundwork for finding a drug for peptic ulcer? On the flip side could SK&F claim that, as there was every possibility of its market monopoly being upstaged, it should be permitted to recover its costs at the earliest? In view of this should the company be allowed to price a tablet of cimetidine at $100 a pill?

R&D – WESTERN BIAS

It would be unfair to see the Indian Supreme Court verdict as a triumph of left-liberal altruism against Western capitalism for several reasons. Firstly, US courts too held that derivatives of known substances are not eligible for patent protection under the ‘doctrine of inherent anticipation’. Also in the US a patentee cannot claim rights for more than one substance with identical claims, under the ‘doctrine of double patenting’. The third principle governing US jurisprudence in relation to intellectual property rights is the ‘patent misuse doctrine’, which prevents pharmaceutical companies from extending their patent rights by obtaining multiple patents covering essentially the same invention. In her extensively researched paper, Trials And TRIPS-ulations: Indian Patent Law And Novartis AG v. Union Of India, (Berkeley Technology Law Journal, Vol: 23. Mar 21, 2008. 281-313), Lynda L. Lee opined that the stand of the Indian courts ‘indicates that the objective of India’s Section 3 (d) is not a radical departure from international practices to regulate the patenting of derivatives and new uses.’ It must be noted that the article was based on the Madras High Court judgment and written much before the final verdict of the Supreme Court.

The reaction of Novartis to the Supreme Court judgement appeared a bit peevish. In a press statement, the company’s Vice Chairman warned that it will discourage R&D spending by multinational companies in India. This is a bit surprising as multinational companies may have been using India as low cost hub for manufacturing and conducting clinical trials but never seem to be bothered about diseases specific to India. For a long time the healthcare fraternity has been complaining that multinational companies focus on diseases prevalent in the western world for researching remedies. For example, we have not seen new drugs introduced to combat malaria and tuberculosis which are endemic to countries like India, in years. The incidence of both the diseases is seeing virulent, intractable forms. Today tuberculosis resistant to multiple drugs – multidrug resistant TB or MDRTB is quite prevalent. On the other hand new drugs for cancer, diabetes and hypertension and related diseases are introduced by the dozen every year.

R&D – ALTRUISM OR BUSINESS STRATEGY? THALIDOMIDE TO GATIFLOXACIN

Multinational companies which have been assuming moral high ground for their altruistic R&D efforts ‘to ameliorate pain and suffering of humanity’ have also been guilty of destroying the lives of millions of people for short term gains.

The introduction and withdrawal of thalidomide is a classic example. In the 1950s, Distillers & Co (the makers of Johnnie Walker whisky) purchased Grunenthal, a small German pharmaceutical company. Grunenthal developed a tranquiliser named thalidomide which was then believed to be so safe it could be prescribed to pregnant women to relieve them of morning sickness. It was introduced in several countries in Europe and freely prescribed for pregnant women. In the early sixties a causal link was established between the use of thalidomide and delivery of malformed babies. This property of a drug which causes foetal abnormalities known as teratogenicity, was unknown till then. By 1961 an estimated 10000 to 20000 thalidomide babies were born and the drug was withdrawn. 

The thalidomide story should have warned the managements of pharmaceutical companies to be extra careful in vetting and promoting their products. But alas no, drugs with serious adverse effects have been introduced by pharmaceutical companies with unceasing regularity. Here are a few examples, some of which may not be as lethal as thalidomide: Analgin (like penicillin) is known to cause anaphylactic reactions so severe a single tablet could kill a patient. Anti-inflammatory drugs like oxyphenbutazone and phenylbutazone have been known to cause blood disorders. However all these drugs were marketed by multinationals in India for a long time after they were banned in their home countries. The newer pain-relieving drug, nimesulide has been banned in several European countries but is still marketed in India (however not by multinationals, but by Indian pharmaceutical companies). Terfenedine, introduced as an advanced, non-sedating anti-allergic had to be withdrawn a few years later as it was found to cause heart-problems. The latest in the series of drugs to be withdrawn was the antibiotic gatifloxacin, which was found to cause cardiac problems. Illich mentioned in his book that the American innovator of chloramphenicol (trade name, Chloromycetin) marketed the drug for simple conditions like acne. Originally introduced for treating typhoid, the drug is known to cause bone-marrow depression. (The human body produces red-blood cells in the bone-marrow.)

PRICING DRUGS

An argument that was vociferously voiced in the television debates relates to pricing; especially that pharmaceutical companies which spend millions (billions?) should be allowed the freedom to price their products. And any regulation would be a disincentive for them to introduce newer products. This argument lacks substance because the pricing of drugs is not uniform even in the western world. For example the prices of drugs in Canada are far lower than the corresponding prices of drugs in neighbouring USA. In some cases the Canadian prices are about half of their American counterparts.

The marketing of anti-retroviral drugs (used to treat AIDS) in South Africa offers an object lesson for those who blindly take sides with the advocates of free-pricing. Indian companies like Cipla and Hetero Drugs offered to sell a combination of anti-retroviral drugs @ $350 for a year’s course. Four multinational companies challenged them in the South African Supreme Court, on the ground that these companies were infringing their patent rights. They were selling the drugs @ $10,000 for a year’s course. They had to withdraw their suit following worldwide revulsion. For, more than a third of the world’s AIDS population lives in Sub-Saharan Africa.

In the television debates, medical doctors representing Novartis claimed that the company has a scheme for providing the medicine free of cost to ‘below poverty line’ patients. This is not entirely true because the company stopped providing imatinib free after two Indian companies were permitted to introduce low cost alternatives in 2006. (See the research paper cited above.) Even if the company has been providing the medicine free to BPL patients, how does one define a BPL patient? Certainly a household with an income of Rs 50,000 per month cannot be considered BPL? If the household has a patient who requires imatinib, can it expend Rs 1.20 lakh a month? Besides, many cancers require multiple regimens of treatment, which include chemotherapy (drugs), radiation and surgery. The latter two are even more expensive than the cost of medicines.

TAILPIECE: By the by, the promotional or marketing budgets of pharmaceutical companies exceed their R&D budgets by a long chalk.   
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This article originally appeared in VOXINDICA on April, 04, 2013