Choking the Patients???


SpicyIP, has in several posts, discussed the issue of generic drug companies taking patients for a ride. The Hindu now reports another instance involving two drugs, theophylline and doxofylline, both of which are prescribed to treat wheezing, shortness of breath, and difficulty in breathing caused by asthma, chronic bronchitis, emphysema, and other lung diseases. Both relax and open air passages in the lungs, making it easier to breathe. In short, they are bronchodilators.
Theophylline, a scheduled drug, and all its derivates such as etofylline, theobromine, oxtriphylline, dyphylline, enprofylline, etamiphylline, proxyphylline and pyridofylline are subject to price control under the NPPA regime. In May 2006, The Hindu reported the launch of doxofylline, popularly known as “Doxobid”, a hitherto unknown derivative of theophylline by Dr.Reddy’s Laboratories under licence agreement from Kent Union Ltd, Hong Kong, and marketing co-operation with Netherlands-based Eurodrug Laboratories BV.
According to The Hindu, since doxofylline is not covered under the NPPA, generic manufacturers are making a killing by aggressively promoting it over its cheaper version theophylline. Quoting Dr.C.M.Gulati, Editor of the medical journal, Monthly Index of Medical Specialities, The Hindu explains the reason for doxofylline’s entry into the country:
The answer lies in the way drug prices are determined and controlled in the country. Doxofylline is being offered as a more profitable alternative to theophylline, prescribed to prevent and treat wheezing, shortness of breath, and difficulty breathing caused by asthma, chronic bronchitis, emphysema, and other lung diseases. It relaxes and opens air passages in the lungs, making it easier to breathe.”
“Theophylline and etofylline – molecules approved for sale in over 200 countries after having undergone rigorous post-marketing trials — are scheduled drugs and subject to price control by the Government. By successive orders in 2006, all loopholes to sell theophylline products at high profit margins have been closed by the National Pharmaceutical Pricing Authority (NPPA), the body that monitors medicine prices in India. Therefore, nearly all companies selling theophylline formulations have been scouting for similar molecules outside the price control system irrespective of whether they are similar, better or even worse than their current brands”
This means that where on one hand theophylline is sold at Rs.6.40 a strip; doxofylline costs patients a cool Rs.80 per strip. Dr. Gulati further adds:
The core issue is profits, not patients. The strategy is to stop selling less profitable, price-controlled products and replace them with hugely profitable alternatives of the same class. Doxofylline fits into this tactic. A molecule which is not even considered fit for mention in standard textbooks is being paraded as if it is major advancement in the treatment of asthma,”
The Hindu also reports that:
Doxofylline bulk drug is not a patented medicine and can be purchased in tons in China at a very low cost without any licence. Yet to give it an international foreign flavour, some drug companies in India have proudly announced that their brands are being produced “under licence” from overseas entities.

The article concludes thus:
Doxofylline is just another derivative of theophylline in this chain and resembles the parent compound in its mode of action, efficacy and safety profile.

The available open literature on the last observation seems to indicate otherwise. An article in PubMed compares the safety of doxofylline and theophylline in treating chronic reversible asthma and on the basis of the results concludes that doxofylline is endowed with a remarkable bronchodilator activity with less extra-respiratory effects than theophylline. It further states that:

This study provides evidence that doxofylline 400 mg t.i.d. is an effective treatment for relieving airway obstruction and displays a better safety profile with respect to theophylline 250 mg t.i.d. with a favorable risk-to-benefit ratio.”

Another journal paper concludes that doxofylline, unlike theophylline, does not affect gastric acid secretion. Where theophylline can cause upset stomach, stomach pain, diarrhea, headache, restlessness, insomnia and irritability, a paper by a research group from AIIMS reveals that doxofylline has significantly lesser side effects. (Of course, one can always question if the reduction in side effects justifies the price of the drug). If a person casts aspersions on the integrity of these results, it would be a weak line of defense unless he has enough material to substantiate his claims.

In addition to this, doxofylline is not an Over-The-Counter (OTC) drug; it is a prescription drug. This means that the drug can be administered only if a physician has prescribed it and this he does despite knowing fully well that a less-expensive alternative in the form of theophylline exists. Ergo, either he believes that doxofylline is better for his patient notwithstanding the higher price, or he wrongfully furthers the cause of generic companies. If he resorts to the latter, he would be guilty of unethical conduct under Chapter 1 and Chapter 6 of the Code of Medical Ethics laid down by the Medical Council of India. Thus far, we do not seem to have come across instances of such conduct involving doxofylline.
That apart, there exist several instances where derivatives of a drug have been sold at different prices on account of either increased efficacy or reduced side-effects, penicillin being a prominent example has 12 or more derivatives. Such being the case, to say that the company has invested a fortune in “developing” something which already exists solely in the belief that it can take the public for a ride sounds too far fetched a proposition, and in these days of increased consumer awareness, insults the intelligence of the public. In the light of these observations, it may not be easy to point accusatorial fingers at generic manufacturers. I do not deny that there have been instances in the past where even Judas would have been put to shame by the conduct of generic manufacturers, but one cannot base that as a premise in every case, however tempting it may be. “He is bad and so he is bad” kind of argument may not hold water.

10 comments.

  1. AvatarAnonymous Coward

    “… to say that the company has invested a fortune in “developing” something which already exists solely in the belief that it can take the public for a ride sounds too far fetched a proposition, and in these days of increased consumer awareness, insults the intelligence of the public.”

    “Oh, who’s being naive, Kay?” seems to be apt response. You need to brush up on Econ 101. The sole basis for price-fixation is the willingness of the consumer to pay. Input costs and cost of development, etc., have nothing to do with price (except that price can’t go down below the input cost). Further, you don’t seem to be dealing with the question of spurious licences which this article brings into question.

    And, “Thus far, we do not seem to have come across instances of such conduct involving doxofylline.” How many instances of such conduct have we come across involving any drug? Please let’s not delude ourselves as to the amount of pressure that doctors face from pharmaceutical companies, nor about the efficacy of the Medical Council of India. Oftentimes doctors themselves run the nearby pharmacies. While this makes things easier for the patients, it also acts as an incentive to prescribe the more expensive drug. Are you seriously saying that you have never been told by one doctor that the drugs prescribed by another are either unnecessary or that they have cheaper substitutes?

    Reply
  2. AvatarJ. Sai Deepak

    Hi there,
    It certainly looks like I have got myself behind the eight ball, but let me try and justify myself. I agree with the broad idea you are trying to convey, however, I believe that we are talking at cross-purposes with regard to the specifics of this case.

    1. There can be absolutely no argument on the issue of over-pricing of drugs and as you have rightly pointed out, the price of the drug need not always have a proper co-relation to the amount of value-added to it and the costs incurred in such value addition, since if that were to be the assumption, there would be no necessity for an NPPA. However, the point which I was trying to convey was that there are several instances where derivatives could cost more than the parent drug for pretty valid reasons and doxofylline could very well fall under such a category. More importantly, this is substantiated by the literature, which rates doxofylline better than theophylline.

    2. With specific regard to the issue of doctors being pressurized by pharma companies to sell their drugs, I think the post was pretty clear on that, for I have acknowledged the possibility of doctors furthering the interests of the companies either under pressure or willingly. I do not believe that merely because such instances have not been reported, they do not exist. But until the time we have concrete proof with specific regard to this case, to make a blanket statement saying that in every case, the doctor and the companies are necessarily and invariably in cohoots with each other and are out to swindle the patient is too unfair a judgment. If you look at the tone of the article in The Hindu (particularly the last two lines about the safety profile and efficacy) and compare it with what the medical literature says, it would certainly appear that the article is completely oblivious to the literature. Also, this article has a rhetorical feel to it and seems to ride on the current wave of pro-patient mentality, which seems to pervade all over because it is somehow assumed that to be pro-patient, one has to necessarily paint a coloured picture of pharma companies, in the process we end up painting everyone with the same brush; which is why I meant to state that since instances of unethical practices by doctors specifically involving doxofylline have not surfaced as yet and with literature talking positively about doxofylline, it would be short-sighted to cut the head to fit the hat.

    3. Here’s something funny. In the third para where The Hindu quotes Dr.Gulati, it has actually reproduced verbatim the functions of theophylline from http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a681006.html. This means that the correspondent has probably rummaged through the Internet for information on theophylline. Had the person gone through literature comparing both doxofylline and theophylline, the tone of article would have probably been much more balanced. Instead, the article relies solely on Mr.Gulati’s opinions. With specific regard to this case, do you have material, which proves that doxofylline is indeed overpriced and that it does not differ significantly from theophylline? If yes, I should have no qualms agreeing with you. If no, my point still stands valid. And yes, economics certainly is not one of my strong areas, may be you could help me with that, but then how can I learn from an anonymous coward? 🙂

    Cheers,
    J.Sai Deepak.

    Reply
  3. AvatarAnonymous

    There is an important point that we might be missing here. The markets in prescription drugs are often skewed in favor of the companies that launch them first (innovative), or those that manage to sell it through docs. The consumers have little choice to go in for cheaper substitutes (even if available)due to information asymmetries in prescription drugs markets.

    Reply
  4. AvatarAnonymous Coward

    1. I agree completely. The question as to whether doxofylline actually falls within this category is out in the open, primarily for lack of data. How the cost (which, let me remind you, is 12.5 times the cost of theophylline) splits up (licence, profit, etc.) has to be ascertained for any meaningful conclusion to this question.

    2. & 3. The article relies on only one source, and does not even attempt to be objective. The Hindu pushes forward a particular agenda. Had an article been published in Mint or TOI based solely on Dr. Gulati’s report, it would still have read very differently. Newpapers have their biases. No one is contesting that. But while you survey a wider range of literature than Ms. Perappadan, your attempts at objectivity seem rather half-hearted. (“I do not deny that there have been instances in the past where even Judas would have been put to shame by the conduct of generic manufacturers,” doesn’t cut it as full-hearted objectivity for me).

    The argument (leaving aside the rhetoric) proceeds as follows (logically, even if not explicitly laid out as such in the Hindu article):
    1. Doxofylline is no better than theophylline.
    2. Even if it is better, it should not cost that much because it is not patented.

    You dismiss the second argument with a mere, parenthetical “(Of course, one can always question if the reduction in side effects justifies the price of the drug).” The Hindu article acts as a straw man to your attack because of the lack of research that has gone into it, and the non-availability of the piece by Dr. Gulati. You are taking on too less a burden, a point I shall get back to later.

    In an IP law blog I would expect more attention to have been given to the following bit:
    “Doxofylline bulk drug is not a patented medicine and can be purchased in tons in China at a very low cost without any licence. Yet to give it an international foreign flavour, some drug companies in India have proudly announced that their brands are being produced “under licence” from overseas entities.”

    Lastly, by saying “… do you have material, which proves that doxofylline is indeed overpriced and that it does not differ significantly from theophylline?” you are reaching the same position as Ms. Perappadan, only from the opposite direction. There would be no meeting ground if both of you sit around waiting for proof, and claim that you are right until proven otherwise. Sure, her article lacks a lot. But having noted that, shouldn’t you take care to make sure yours doesn’t lack similarly?

    It might well be that doxofylline is much better, and that it’s bloody expensive to license and manufacture. But I do have problems with your never reaching that conclusion — you are contented with showing that the article is not necessarily correct in its conclusions. The conclusion that I would have liked to see you reach would have been either: The Hindu article is plain wrong — the drug is much better, and should cost that much; or The Hindu is partially wrong — the drug is much better, but frankly it shouldn’t cost that much.

    I realise that might be a bit too much to ask, but I believe it is in the collective best interst to be that demanding. I hope all this doesn’t come across as a personal attack, because it isn’t meant to be.

    Cheers,
    Anonymous Coward

    Reply
  5. AvatarJ. Sai Deepak

    Hi A.C,
    I see your point; you would rather have me build my case on its own merits rather than by pointing to the chinks in The Hindu article. The point is well taken and well received though I would like to clarify that my intention was not to lampoon or to lend some kind of a conspiratorial colour to a reputed publication such as The Hindu. It would be in our best interests if we could restrict this discussion to the nature and content of the article and the issue in question. Also, the question of me viewing your comments as a personal attack should not arise for we in SpicyIP believe that a demanding customer is an organization’s greatest asset; so, it’s a good sign that our readers, who more often than not, are better informed on most issues, haul us up whenever we err.

    Now, lets get down to the brasstacks. As you have rightly pointed out, ideally I should have reached or atleast attempted to reach either of these conclusions:

    1. Doxofylline is much better than theophylline and there are valid reasons for the high cost
    2. Despite doxofylline being much better than theophylline, it could certainly cost lesser.

    Before posting on the issue, I did a preliminary search on patents on or related to doxophylline/xanthine derivatives/methylxanthine etc. with reference to their anti-asthmatic action and it appears that there are a few process patents/method of manufacture patents on the same such as US5160469 and about 10 more. This was to verify if there were/are any product patents on doxofylline and there are none. Consequent to your comments, I decided to look for more information and the following is what I have learnt.

    Before I proceed, here are a few statistics:

    Doxofylline 400mg (10’s strip/blister) (Brand-Manufacturer-Prices in Rs.)

    Indian Manufacturers

    1. Doxobid- Dr.Reddy’s- 83
    2. Synasma- Ranbaxy- 79.50

    Global Prices in (Brand-Manufacturer-Prices in $)

    1. Puroxan Tab-Eurodrug- 7.5
    2. Maxivent- NA-NA
    3. ZorDox-NA-NA

    Theophylline 400mg (10’s strip/blister) (Brand-Manufacturer-Prices in Rs. BEFORE NPPA)

    1. Od Phyllin- Sun Pharma- 40
    2. Duralyn CR- Raptakos Brett- 47
    3. Lontif- Strassenberg- 40
    4. Phyloday- Wockhardt-45
    5. Theoday- Protech Biosystems- 28
    6. Theoresp- Lifemedicare-44
    7. Thp-1- Kee Pharma-29.80
    8. Tsr-400- Bestochem-44
    9. Unicontin- Modi-Mundi-66.72
    10. Vent-T- Kresp-68

    Global Prices in (Brand-Manufacturer-Prices in $)

    1. Aerolate-NA-9.3
    2. Aerolate Theo-24- NA-7.1
    3. Quibron T-NA-5.4
    4. Uniphyll-NA-8.5

    From the figures, we see that ever since doxofylline was first introduced in India in May 2006, i.e. almost 2 years, only 2 entities have undertaken its manufacture and sale, namely Dr.Reddy’s and Ranbaxy, under the trade names Doxobid and Synasma respectively. The former costs Rs.83 per 10’s strip/blister, and the latter is priced at Rs.79.50 for the same quantity at 400mg dosage. In comparison, the number of Indian generic manufacturers of theophylline is 5 times greater than that of doxofylline.

    Hypothetically assuming that there is no technology barrier to the manufacture of doxofylline, all these manufacturers of theo (in short for theophylline) should have switched to manufacturing doxo (in short for doxofylline) given that it is not covered under NPPA. (This would have even brought down the price of the drug under normal circumstances unless each company decided to make the most of the demand). However, such a switch hasn’t taken place, which means that probably there is more to the technology than we understand. May be the replacement of the hydrogen group in theophylline by the aldehyde group to obtain doxofylline is not easy (this again is not conclusive for I am no expert in pharmacology or chemistry). This could also be a reason that entities such as Suven Pharma import doxofylline rather than manufacturing it. However, technology barrier need not be the sole reason for importation since if importation is cheaper than manufacturing, one would rather resort to the former. Here again, I would like to clarify that my attempts at identifying the players do not amount to name dropping for my sources are the current edition of Current Index of Medical Specialties (CIMS) prescriber’s handbook and online directory of pharmaceutical manufacturers. To cut a long story short, one needs more information on technology to conclude if it is the reason for the higher price.

    Next, the price of theo 400mg under NPPA is Rs.6.40 which as you pointed out is 12.5 times cheaper than doxo 400mg. It must be pointed out that you have compared the price of theo under the NPPA with the price of doxo which is not covered under NPPA. This may not give a complete picture since although the NPPA price fixation procedure leaves room for some amount of profit (about 14% on networth), it cannot be denied that it is far below what the companies could charge (assuming that they are within reasonable limits and the ceiling fixed by the govt. cannot be taken as the ideal limit). So, I would rather have you compare the prices of theo prior to the NPPA with that of doxo. From the figures, we see that the maximum price of theo 400mg was approximately Rs.68 before it was made a scheduled drug and this compares reasonably with Doxobid at Rs.83. Of course, one might say that when theo was made available at Rs.28, it does make doxo’s price seem unreasonable (It follows that the manufacturer was still able to make decent profits at Rs.28). This is a question of branding and companies such as Reddy’s and Ranbaxy do charge for their brands. Therefore, though not conclusive, a technology barrier, a license fee, tax on the license, import duty and brand together could justify the price of doxofylline.

    It suddenly struck me that one could also compare the global prices of these drugs and if doxo’s price is significantly higher than theo’s price, one could argue that the trend is being merely replicated in India. From the figures, we see that Eurodru’s Puroxan, which is doxo 400mg, costs $7.5 a strip and Quibron-T, which is theo, costs $5.3. However, this could be misleading because certain brands of theo cost more than doxo. In addition, it might well be that our generic manufacturers are capable of flattening these prices in India thanks to cheaper manufacturing costs. Once again, I don’t see myself reaching a confident conclusion.

    Before I proceed further, I would like to point to another key issue. This entire comparison was between the prices of Theo 400mg and doxo 400mg. Why? Is it because the quantities in question are the same? Is the effect of theo 400mg the same as doxo 400mg? This takes us back to the literature, which says that the efficacy of theo 250mg is the same as doxo400mg with the latter displaying reduced side-effects. So we should actually be discussing the prices of theo 250mg and doxo 400mg. However, that would still lead us nowhere for we do not know the actual price and the technical parameters under NPPA on the basis of which the ceiling was fixed. (btw, theophylline 250 mg under the name TR Phyllin was priced at Rs.9.05 prior to the NPPA)

    Then I realized that all these conjectures and hypotheses would be hanging in mid-air without first-hand information from either a general practitioner or a manufacturer. I went for the former. I spoke to Dr.Ajay Patwardhan, the Medical Director at GE’s John F.Welch Technology Centre, Bangalore and explained the issue to him. The good doctor was kind enough to bear with me and for the next 35 minutes, I got the most comprehensive low-down on what actually happens on the ground and I must admit his crisp answers were proof of all the wisdom he had acquired in over 3 decades of practice. His answers also showed that some of my assumptions in the post were overtly academic and hence were largely divorced from ground realities. I would like to reproduce the conversation in a QnA format. Please note that this is not a verbatim reproduction and I am merely presenting the gist of what he said with no attempts whatsoever at “doctoring” or distorting the doctor’s words.

    “Me: Is doxophylline better than theophylline?
    Doc: The question is not irreducible and needs to be broken down further. Move a step back and ask why did the doctor decide to opt between either of these drugs without going for an alternative option?

    Me: Can you please elaborate on that?
    Doc: These drugs are bronchodilators and the market for bronchodilators is on the wane. These days most doctors prescribe inhalers with salbutamol combinations because they are safe and are much more effective in preventing asthmatic attacks. Only when the doctor feels that the patient cannot do with anything other than these bronchodilators, he would prescribe them.

    Me: This brings me to the question of “prescription drugs”. Can I purchase these drugs without a doctor’s prescription? Also, is the penetration of inhalers the same in urban and rural areas?
    Doc: On the first question, in India, it’s a big YES! There are two reasons for this. One, because the enforcement of these rules is lax and two, because of increased patient awareness which means instances of self-medication are extremely high. See, you must understand that diseases such as asthma are chronic ailments and patients are extremely familiar with the literature given their long medical history and sometimes they don’t need the doctor. Also, most of these patients are always on the lookout for better alternatives and so they keep scouting the market for information. Such being the case, prescription or no prescription, they get what they want. As long as the patient is outside the hospital, he rules the market; once he enters the hospital, the doctor dictates his choices. But it should also be borne that the comfort level of the patient with a particular medicine is another factor that decides his migration from one drug to another. A patient in the urban area might move from theophylline to doxofylline if he suffers from side-effects of theophylline. For a person who is perfectly fine taking theophylline, the presence or absence of doxofylline makes no difference at all. Also, theophylline is usually given in combinations and if the doctor wants to reduce the side-effects of theophylline 250mg, he could give a combination of theo 100mg and rest comprising salbutamol or ephedrine without directly jumping to doxofylline. Then again, this is very subjective.

    The same logic, in a slightly altered fashion, has to be applied to your second question. People in the rural areas might be wary of inhalers even if the doctors prescribe it and might ask the doctor to “prescribe” bronchodilators if they are comfortable with it! This explains why inhalers have a greater presence in the urban areas than in rural areas, but the rural market too is on the rise. There’s another factor-money. If a patient has problems with theophylline, he wouldn’t think twice before shelling out a hefty amount for doxofylline if it means better relief even if he has to beg, borrow or steal. Similarly, if he can afford to pay Rs.500-700 a month for inhalers, he might opt for it.

    Me: What about instances where the doctor is hand in glove with manufacturers and deliberately sells a higher priced drug? How often do these things happen? Can you give me your opinion on the ethical market and the grey market?
    Doc: Don’t expect anything in black and white here. Ranging from a pen to a fully-paid vacation to Singapore along with your family and an opportunity to speak at seminars, they are multifarious ways in which you can be “pressurized”. As regards, prescribing a higher priced drug, take the case of a Hepatitis-B vaccine. A doctor can purchase 10ml of it manufactured by a prominent brand at say Rs.180. If an individual buys it, it would cost him Rs.250. The doctor would buy the drug from a generic manufacturer at Rs.45 or Rs.120 and sell it to the patient at Rs.250 including his consultation fees.

    Me: What about the Code of Medical Ethics stipulated by the MCI?
    Doc: 30-40% of medical practitioners are not subject to the Code for they practice alternative medicine. Also, a doctor may always contend that he did what he felt was best for his patient and there’s practically no way you can prove otherwise. See, beyond a point if the doctor prescribes something that is ineffective, he is bound to lose the patient’s confidence in the long run. Reputation takes precedence over money after the first few years of practice because such professions are built on reputation.”

    Though the core issue of price has not been answered here, I believe the exercise was worth it. From the above conversation, one can possibly infer that since the market for bronchodilators is on the wane, most theo manufacturers have not shifted to doxo and those already manufacturing doxo are making hay while the sun still shines. One might say that I still haven’t reached either conclusion. True, that’s because I need more information. But I certainly believe that I have given as objective a picture as I could, given the limited resources at my disposal.

    For the benefit of our readers, kindly share any information you have or your views on the same.

    Wishes,
    J.Sai Deepak.

    Reply
  6. AvatarJ. Sai Deepak

    A.C,
    Is there a way of finding out if any manufacturer other than the ones mentioned has applied for a regulatory approval to introduce doxofylline in India? If yes, please let me know. By the way the issue of spurious licenses was not covered because other than the entities mentioned, there doesnt seem to be much information available on entities which have taken a licence for importing doxofylline and i rather wait patiently for information rather than grope in the dark. Probably, Dr.Gulati could shed light on this.

    I would also like to add another point. You said “you are reaching the same position as Ms. Perappadan, only from the opposite direction. There would be no meeting ground if both of you sit around waiting for proof, and claim that you are right until proven otherwise”. Don’t you think what you expect me to do amounts to a “adverse reversal of burden of proof” if i may call it so? If someone has a problem with a drug being sold at a higher price, one would expect the person to show why such a price is unreasonable rather than ask the manufacturer to prove that his price is unreasonable. Of course, i do not deny that i could have articulated further on my arguments.

    J.Sai Deepak.

    Reply
  7. AvatarJ. Sai Deepak

    A.C,
    Is there a way of finding out if any manufacturer other than the ones mentioned has applied for a regulatory approval to introduce doxofylline in India? If yes, please let me know. By the way the issue of spurious licenses was not covered because other than the entities mentioned, there doesnt seem to be much information available on entities which have taken a licence for importing doxofylline and i did rather wait patiently for information than grope in the dark. Probably, Dr.Gulati could shed light on this.

    I would also like to add another point. You said “you are reaching the same position as Ms. Perappadan, only from the opposite direction. There would be no meeting ground if both of you sit around waiting for proof, and claim that you are right until proven otherwise”. Don’t you think what you expect me to do amounts to a “adverse reversal of burden of proof” if i may call it so? If someone has a problem with a drug being sold at a higher price, one would expect the person to show why such a price is unreasonable rather than ask the manufacturer to prove that his price is reasonable. Of course, i do not deny that i could have articulated further on my arguments.

    J.Sai Deepak.

    Reply

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