Pioglitazone: The Saga Continues

The Ministry of Health and Family Welfare (MoHFW) India issued a notification on June 18, announcing the suspension of manufacture for sale and distribution of oral anti-diabetes drug pioglitazone and all the formulations containing it for human use in India. It came as an unwelcome surprise to not only the pharma companies who were manufacturing or marketing the drugs but also for medical professionals who were prescribing it on a day to day basis and last but not the least, the diabetic patients who are on pioglitazone medication. To challenge the ban, medical experts in association with patients, pharma stakeholders and diabetologists came together and made pro-pioglitazone representations to the MoHFW and after speculations on these arguments, the ministry revoked the ban officially on July 31, but with cautionary mandatory guidelines on each pack.

The news of the revocation of the ban on pioglitazone was a cause for celebration for many. Responding to the announcement, Dr Rajiv Kovil, Founder Member, United Diabetes Forum, Dr Kovil’s Diabetes Care Centres says, “This decision will bring a smile back on the face of 30 lakh patients who are using the drug. Diabetes specialists across the country believed that pioglitazone is a nuclear level good molecule which when used judiciously can produce excellent results. It is a victory for science which brings the patient-doctor relationship much closer. This saga and red box warning will ensure the judicious use of pioglitazone and all molecules in the chronic care segment, thus ensuring transparency and evidence-based practice.”

“I believe that physicians must use it very judiciously and not rampantly as it was used earlier.” Dr A K Singh Consultant Endocrinologist and Diabetologist, GD Hospital and Diabetes Institute, Kolkata and Sun Valley Hospital and Diabetes Research Center

Dr A K Singh, Consultant Endocrinologist and Diabetologist, GD Hospital and Diabetes Institute, Kolkata and Sun Valley Hospital and Diabetes Research Center expresses, “I am happy that the pioglitazone ban has been revoked officially through notification in the Indian Gazette Extraordinary dated July 31. Now it will help all of us to control and manage diabetes effectively.”

Why was pioglitazone banned in the first place?

“Every one who resisted the ban believed that the drug has a lot of value, especially in India where it is a cheap drug with a long durable action.” Dr Rajiv Kovil Founder Member, United Diabetes Forum, Dr Kovil’s Diabetes Care Centres

The Health Ministry’s decision to ban the manufacturing and sale of pioglitazone drug was reportedly due to its ban in France in 2011 on account of its associated risk of bladder cancer and a report by a Chennai-based doctor, Dr V Mohan. Kovil informs, “France had banned pioglitazone in June 2011 and there were no fresh new evidences to ban it since then, hence it came as a surprise. Majority of diabetologists across the country believed that the Government of India (GoI) had taken a knee jerk reaction and hence made their protest evident through media, social media, petitions and also RTI. There was anger, anguish and despair among patients and doctors across the country when the ban on pioglitazone was announced.”

“All is well that ends well!” Daara B Patel Secretary-General, Indian Drug Manufacturers’ Association (IDMA)

Daara B Patel, Secretary-General, Indian Drug Manufacturers’ Association (IDMA) reveals the steps taken by the association against the ban and says, “In our representation submitted to Drug Controller General India (DCG(I)) earlier requesting them not to suspend the drug, we have highlighted a few studies conducted internationally which point out that the side-effects associated with pioglitazone, such as bladder cancer, was not significant and that there are too few events of bladder cancer reported. However, despite this, leading regulatory agencies such as US FDA, UK MHRA, Japan PMDA and Australia TGA have persisted with its availability in view of its immense need for managing Type II diabetes mellitus (T2DM). The reasons have been based on firm scientific evaluation of the same based on factual evidence.”

Singh agrees with the drug’s side effects and informs, “It is well known fact that any drug administered to a patient will have a side effect. Pioglitazone does have some side effect like pedal edema, macular edema and propensity to aggravate latent heart failure. It can also aggravate osteoporosis and incidental fractures in postmenopausal women and therefore needs caution. An astute physician will choose the right patient for a given therapy to avoid the side effects.”

Risk vs acceptability

“It is the responsibility of the DCGI to protect patients, not profits and sales of the pharma industry.” Dr Chandra M Gulhati Editor, MIMS

Dr Chandra M Gulhati, Editor, MIMS imparts more information on the pioglitazone ban and highlights, “The notification (of June 18) had merely stated that continued marketing of pioglitazone can harm the patient. And the ministry has not given any reasoning for ‘suspension’ of marketing authorisation. There must have been very good reasons to suspend the manufacture, distribution and sale of pioglitazone. The Ministry has ‘not suggested to switch to another treatment methodology’.”

Patel points out, “For any new product, clinical trials are necessarily being carried out to test the drug on Indians even though the drug has been found to be efficacious in overseas market and has a history of use!” He also stated that in this context pioglitazone’s use should be permitted for the benefit of Indian diabetes patients unless the evidence of its cancer concerns far outweighs its utility. He further added, “It thus seems irrational that even in the absence of relevant data on Indians, the Health Authority considered suspending pioglitazone, based on just one European country (Republic of France) – that too whose health regulatory agency (AFSSAPS) had stated in June 2011 that it was banning pioglitazone since the ‘population of its country particularly had shown an unusual associated risk of bladder cancer with the use of this drug’. Hence, such a premature attempt at prohibiting pioglitazone’s availability in the Indian market was grossly unjustifiable, not only for the consumer but even for the pharma industry which would suffer a setback to the tune of over Rs 550 crores (annually as per ORG, March 2012 – India).”

While recalling the DCGI’s responsibilities and duties, Gulhati queries, “It is the responsibility of the DCGI to protect patients, not profits and sales of the pharma industry. Pioglitazone is one of the many anti-diabetic agents and there are so many other drugs for diabetes. If patients in France and German can survive without pioglitazone, so can people of India. Why should a patient be treated with a drug that can cause bladder cancer?”

Singh disagrees with the government’s opinion and counter-argues, “If the insubstantial association of bladder cancer is the reason for banning pioglitazone then all existing anti-diabetic agents (except metformin,) including insulin, sulfonylureas (SUs), and incretin-based therapies should be withdrawn or banned as well because of their unsubstantial associations with cancer. All current major international guidelines, including ADA/EASD (2012) and IDF (2012) recommends pioglitazone as a second line drug after metformin.”

He continues and informs about the drug’s side effects and suggests, “When everything hinges on the risk-benefit ratio, it is tilted heavily in favour of pioglitazone. The number of patients required to be exposed to pioglitazone to cause one bladder cancer is very high when compared to the number of deaths prevented by its meticulous use. I believe that physicians must use it very judiciously and not rampantly as it was used earlier. It should be used in the lowest effective dosage whenever applicable and must not exceed doses of more than 30 mg/day. Everybody should be aware about the ‘Red Box warning’ associated with its use and always remain pharmacovigilant about all the side effects.”

Why India needs pioglitazone

Pioglitazone is a preferred drug for diabetes treatment as it is the cheapest drug available in the Indian market. According to the ORG 2012 data, the consumption of pioglitazone in India alone is 2,84,81,000 units and its combinations is 8,97,90,000 units annually. This translates into approximately 3.25 lakhs patients consuming pioglitazone/-based combinations every day of the year! Informing about the availability of pioglitazone with its price variation in the Indian market, Singh says, “For a month’s treatment, pioglitazone nearly costs Rs 120-150 as compared to other oral drugs like gliptins which cost Rs 1200 -1300 for a month or injectable GLP-1 analogues that cost Rs 4000-4200 per month. It is an effective oral drug and banning this drug obviously would lead to much increased utilisation of either gliptins or GLP-1 analogues, incretin-based therapies (long term safety still unproven apart from being costly) or insulin (injections, regular monitoring, complex regime). Today lakhs of Indian diabetic patients are on pioglitazone treatment with no untoward effects.”

Patel points out, “Discontinuing pioglitazone can result in unwarranted poor hypoglycemic control, leading to more defined health related concerns in Indians, with India already recognised to have the largest population of diabetics, This evidently implies that the medical profession is more dependent on pioglitazone (and combinations) for managing their T2DM Indian patients. ”

“I am very glad that the drug is available again in the market.” Dr Banshi Saboo Fellow – American College of Endocrinology, Diabetologist and Endocrine Physicians

Dr Banshi Saboo, Fellow – American College of Endocrinology, Diabetologist and Endocrine Physicians opines, “The sudden ban left us with no options at all and patients, as an alternative, had to be put on gliptins or insulin to help control their diabetes. It caused a sense of dilemma and mistrust in the minds of the patients as to why did their doctor prescribe them a drug with such a dangerous side effect. For the patients from the unaffordable category it was even more difficult as gliptins and insulin are costlier than pioglitazone. It left our patients with uncontrolled blood sugar levels and anxiety. The upliftment of the ban from the drug has been a relief overall. I am very glad that the drug is available again in the market.”

Kovil emphasises, “Every one who resisted the ban believed that the drug has a lot of value, especially in India where it is a cheap drug with a long durable action.”

Pharmacovigilance: a needed step

Gulhati informs, “Tracking hitherto unknown side effects of marketed drugs is an extremely tedious, time consuming, expensive and elaborate exercise. Depending on drug manufacturers, with obvious conflict of interest, to report adverse drug reactions (ADRs) on their own products is unwise. Experience in the past has taught that depending on spontaneous reporting of side effects by physicians, pharmacists, nurses etc. is not adequate. Even in the US, not more than 10 per cent side effects are reported spontaneously. The answer lies in large scale, controlled, phase IV trials focused on identifying side effects. There has to be an independent mechanism in place, run and managed by academic institutions with no biased interest. This is the only way forward. “

He continues, “The current pharmacovigilance (PV) programme in India is ineffective. As of date there is no way except drawing on the experience and reports of side effects and regulatory action taken by advanced countries. The MoHFW has correctly taken a decision to suspend marketing of drugs which are prohibited in specified developed nations viz US, Britain, Canada, EU, Australia and Japan.” (More details of the challenges facing India’s PV framework are in the story, ‘Pharmacovigilance: Is India losing the way?’, pages 15-21 of this issue)

Media’s role

Patel enlightens that Dr V Mohan, the doctor who authored the report based on which pioglitazone was banned, had vested interests for favouring the ban. He says that as per many newspaper reports, Dr Mohan’s Diabetes Specialties Centre, Chennai was apparently being supported by an MNC who could have had a vested interest in promoting an alternative to pioglitazone. Patel also states that probably it was the first time that our health authorities took such a drastic step without seeking industry’s views or at least consulting the medical fraternity who prescribe this medicine regularly. Any concern of the regulatory/health authorities pertaining to pioglitazone could always have been discussed and debated with concerned stakeholders as well as with practicing medical professionals, relevant medical experts and the pharma industry’s representatives.

However Gulhati states that MoHFW had no hidden agenda behind banning pioglitazone. He asks, “A decade ago USV’s phenformin was banned, was it to hurt USV? Besides, both Sun Pharma and Lupin market pioglitazone under the brand names of Pioglit and Path. So, how can they be benefited by banning their brands? To even think that the health ministry’s move is meant to help certain drug companies is beyond belief. It is the direct fallout of media coverage and 59th report of the parliamentary committee on health, which castigated DCGI for dancing to the tune of the drug industry at the cost of the welfare of patients. It is the statutory duty of DCGI to protect the interest of patients.”

Further steps required

Regulatory body of France has taken cognizance of a cohort study by the Kaiser Permanente Northern California (KPNC), which included around 190,000 patients, and showed an increased risk of bladder cancer with pioglitazone exposure for >24 months. However, after adjusting for age, sex and use of other glucose lowering drugs, the association between pioglitazone use and bladder cancer was not significant. Singh suggests, “Physicians must use pioglitazone judiciously in selected cases where it is indicated, preferably not as first or second line agent. Patients with heart failure, osteoporosis and at risk of developing macular edema should not be given pioglitazone. The lower dose of pioglitazone, in combination therapy, could be equally effective and may be used to avoid any cumulative long term risk. We must remain pharmacovigilant. MoHFW, DTBA, DCGI, Journal of the Association of Physicians of India (JAPI) and Association of Physician of India (API) should take lead in increasing awareness. Currently we may put a ‘black box warning’ about these potential side effects to make both patients and doctors aware. However, it is too harsh to ban a potential beneficial drug in diabetes on this unknown and unsubstantiated bladder cancer risk!”

Commenting on the government’s further steps before banning any drugs in India, Gulhati says, “Industry has obvious conflict of interest. Would it ever advocate a ban? As far as experts are concerned, the number needs to be much larger than current levels of a few that can be counted on finger tips. Besides the process of selection of experts has to be transparent. The parliamentary committee has named and shamed many “eminent experts” from medical colleges and hospitals who have merely signed ghost recommendations drafted by drug manufacturers in support of their products. Moreover, even honest experts can only comment on data that is generated abroad. Personal opinions of experts without credible, transparent data and evidence in support of such opinions is of limited use. Unless original, independent, credible data on ADRs is generated in India, there is no practical alternative to mainly depending on data generated abroad in the decision making process.

Patel quips, “Alls well that ends well! It is now learnt that the DTAB, in the meeting on July 19, has endorsed our suggestions and recommended to the Government to revoke the ban. We also understand the Board has recommended that the drug carry a box warning on the possible risk of bladder cancer.” The argument continues but the fact remains that any step taken should ultimately benefit the patient. It also goes without saying that we need to be more pharmacovigilant and that patients should be kept in the loop about the side effects of any medication consumed by them.

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