In a country where regulatory law enforcement is so lax that high-potency antibiotics and injectables are sold over the counter without prescription, the shocking adverse drug reaction incident causing 150 deaths at Punjab Institute of Cardiology attributed to an adulterated anti-anginal drug isosorbide-5 mononitrate contaminated with a lethal dose of anti-malarial pyrimethamine, was an accident waiting to happen.
The 64-million question is: Who is responsible for the impurity in the drug and how did a anti-malarial molecule mix up with an anti-anginal drug? This was not just a blunder, but obviously a case of criminal neglect on the part of the manufacturer. The adverse reaction endemic to PIC was not a random incident that will hopefully not happen again. However, when the drug issue is politicised, it is bound to cloud the real underlying issues.
From a national perspective, the root-cause of the problem can be traced to Pakistan's health budget. At a constant half-a-percent of the GDP and just about 3% of the annual budget for the last 65 years the money earmarked for public health sector is woefully inadequate with negative implications for budgetary health allocation stretched thin to procure the cheapest drugs for a population of 180 million growing at 2%. According to WHO, on purchasing power parity basis, Pakistan government expenditure on health per capita is US dollars 21 that is lower than Nepal [$25], Cambodia [$32], India [$44], Philippines [$48], Indonesia [$52], and Papua New Guinea [$55]. On the other hand, Private Out-of-Pocket Direct Health Cost in Pakistan is 85% of private health expenditure compared with world average of 60%, largely due to lack of medical insurance.
Cheap drugs cost less, in terms of budgets, but they cost a lot more in terms of lives! That is because cheap drugs often lack consistent quality and stability. Safety and efficacy must, therefore, always take precedence over price. Where the medicines are meant to be given free of cost to the patient, quality is invariably sacrificed for lowest price, with fatal consequences for the poorest strata of society.
Ethicals and corporate social responsibility (CSR) Manufacturing medicines is essentially different from other consumer products because drugs basically save lives but may also have serious side-effects, contra-indications, and interactions. Because their manufacturing and marketing involves the highest level of social accountability, drugs are also called Ethicals. Therefore, there can be no compromise in quality on ethical grounds, even if the company must sometimes forego profit.
On the corporate front, however, the Pakistan Pharmaceutical Manufacturers Association also failed in their corporate social responsibility for a serious lapse in quality control which is still a grey area for a large number of generic manufacturers. As an industry watchdog, the onus is on PPMA to do its part to upgrade, enforce and monitor quality management processes in strict compliance with the highest international quality assurance standards according to Good Pharmaceutical Manufacturing Practices [GPMP]. The Iso-tab incident has tarnished the image of the pharmaceutical industry and badly shaken the confidence of millions of patients on regular maintenance drugs for cardiovascular and other serious illnesses.
Of course, manufacturing accidents may not be fully controllable by the companies. The part that is within company's control is how the senior executives of the company decide to handle such accidents as part of their Corporate Social Responsibility or CSR. Effective Crisis Management, therefore, is a critical managerial skill that separates the best companies from the mediocre manufacturers.
No matter how careful any company is, bad things do sometimes happen to its brands. In the 1960 thalidomide tragedy, use of a new tranquilliser in pregnant women caused severe birth defects. In 1986, terrorists laced Johnson & Johnson's top pain-killer Tylenol with cyanide , killing 7 people in the US. The company lost $1 billion in market value but it removed Tylenol from every outlet and replaced it with a tamper-proof pack. In 1990s, The brand that made mineral water chic, recalled its entire inventory from US stores after a chemical benzene was discovered in Perrier bottles. In 2004, after 80 million prescriptions had resulted in 30,000 sudden cardiac deaths between 1999 and 2003 attributed to the breakthrough arthritis drug Vioxx, the pharmaceutical giant Merck decided to take it off the shelf, killing a billion dollar brand instead of killing more patients for profit.
The company making Iso-tab20 obviously failed to learn a lesson from a manufacturing and quality control mistake. To make a bad situation even worse, the management tried to cover-up an obvious quality control lapse with a conspiracy theory about stolen raw materials from the factory. Reportedly, the production manager had waved a red flag on Batch 93 but his warning was ignored. Breaching the trust of the doctors and patients will ultimately cost any company in terms of its corporate image and sales.
Fixing responsibility for the human toll Unfortunately the worst medical tragedy in Pakistan happened particularly at a time when the Drug Regulatory Authority was dysfunctional since the last six months after the devolution of the drug regulatory mechanism in the 18th Amendment. So in effect the pharma sector is still operating in a vacuum. Worse, there is no drug monitoring and evaluation system to take preventive measures and minimise the risk of fatalities. Although the Sindh, Punjab and KPK Assemblies have passed resolutions to constitute a Drug Regulatory Authority at the provincial level, the real challenge they face is to find competent staff to make the provincial DRAs efficiently operational through an effective co-ordination mechanism on a national level.
Irrational pricing policy Does the buck stop at the doors of the health bureaucracy for an irrational pricing policy allowing fat profit margins to proprietary brands and unrealistically under-pricing generic brands of the same molecule thus forcing local manufacturers to cut corners on quality? The originator brands should command a premium for their research, innovation and marketing costs, but the price differential between the brands and generics should be reasonable enough to make both branded and generic drugs affordable for the majority of Pakistanis whose drug expenses account for nearly 50% of disposable income. The pharma industry is enjoying high growth and profitability in the region of 20%, so they owe it to their patients to lower profit margins and bring down prices within reach of the poor masses who spend half of their household income on health.
The Punjab Health Department must take a large part of the blame for not strictly monitoring and evaluating the purchase of essential drugs. Where public money is involved, as it often does in bulk purchase of drugs, the tender issuing authority looks for the lowest quotation, but looks the other way even if the quality of medicines is compromised.
Or shall we fault the manufacturers, distributors and retail chemists for producing, storing and selling drugs below international standards thus converting life-saving drugs into life-taking drugs ? Since 95% of the pharmaceuticals machinery and raw materials are imported, the manufacturers are continuously searching for cheaper sources thus increasing risks of declining quality standards. Due to depreciating rupee, imports are becoming costlier. Some manufacturers may compromise on quality sources of raw materials, including the excipients essential for stability of the product, to compensate for the heavy discounts and kickbacks.
Shall we hold the doctors responsible for administering drugs to patients without taking due precaution about their side-effects and contra-indications that cause adverse reaction? After all, doctors have an ethical responsibility to prescribe quality medicines that are safe and effective. Or should the hospital management be taken to task for failing to test the quality of the drugs supplied before dispensing it to the patients? Or are the poor patients to blame for seeking free medicines and receiving a short deal in poor quality medicines?
Opening flood gates of generic brands In the pharmaceutical business, if the profits are high, so is the cost of innovation. Industrywide research and investment globally exceeds $65 billion. Only one out of 10,000 discovered compounds actually becomes an approved drug for sales. Cost of developing a blockbuster drug is $1.3 billion not including marketing expenses of $0.5 billion. It may take 10 years for a new drug to go from discovery to regulatory approval in three phases of human trials.
Generic drugs are cheaper because they have no R&D or product development and initial market development cost. In the US, 50% of generics are produced by the same branded companies whereas in Pakistan local generic manufacturers are profiting from blockbuster brands after expiry of their patents. However, the Pakistan Generics Drug Act 1972 opened the floodgates of generic drugs to local manufacturers who not only reverse- engineered production processes of the multinational companies [MNCs], but also managed to reverse the market shares in their favour.
In Pakistan, more than 30,000 drugs were registered in the past 30 years. Yet only 345 or just one percent of the drugs are on the Essential Medicines List [EML]. Most of the registered products are generic versions or me-too drugs unleashed by the Generic Drugs Policy. Keeping track of such a colossal number of drugs proliferating the market is an impossible task for any regulatory authority. Several dangerous drugs that had been previously de-listed were reportedly again re-registered by the MOH. In the case of pyrimethamine, for instance, the severe and irreversible effects of pyrimethamine give rise to life-threatening effects and complications including intravascular coagulation, coma, blindness and deafness. The drug is now banned for treatment of malaria but restricted to treating parasitic infection toxoplasmosis. Pyrimethamine may be also be carcinogenic. Yet in Pakistan we have over 50 manufacturers of this drug.
In theory, the pharmacological effects of generics should be exactly the same as the brand name drugs in terms of dosage, intended use, side-effects, route of administration, risks, safety and strength of the original proprietary brand. However, in practice, quality and effectiveness of generics manufactured are often compromised due to substandard supply sources of the salts and shoddy quality control processes.
Pharmaceuticals tops the list of profitable growth industries. Therefore, drug marketing tactics of medicines by both the multinational and local companies have been criticised on grounds of unethical practices from lobbying politicians and bureaucrats to aggressively marketing drugs to physicians for prescription generation, running costly promotional campaigns, and sponsoring doctors for conferences. The pharma industry spent $855 million on lobbying activities between 1998-2006 according to the Center for Public Integrity.
Management of medication errors The King of the Pop Michael Jackson died of a lethal dose of propofol in 2009. Lately, another pop music icon Whitney Houston died apparently of a prescription drug overdose In the USA, over a million people are injured annually due to the so-called 'medication errors'. Unfortunately, there are no statistics available for Pakistan because there is no dedicated Medication Error Reporting and Prevention Body in Pakistan responsible for systematic collection and dissemination of medication error data.
A medication error is any preventable event that may cause or lead to inappropriate medicine use or patient harm while the medicine is in the control of the healthcare professionals related to practice, health care products, procedures, systems, including prescribing communication, product labelling, packaging and nomenclature, compounding, dispensing, distributing, administration, education, monitoring and use. Almost half of fatal medication errors occur in patients over 60 years of age. Older people are at greatest risk of medication errors because they often take multiple medications. However, pharma companies do not sufficiently emphasise the information about the dangers of the drugs to the high-risk groups and leave this vital information to the fine-print of the packing leaflets.
Remedial actions
------ The Health Budget should be increased from 0.5% of GDP to 3% [as in Kenya and Ethiopia] in 2012 Budget and then raised to the level of 6% of GDP [as in Turkey and Korea] by 2015 when the Pakistan population will in all probability cross the 200 million mark.
------ The Drug Act 1976 needs to be updated in line with changing market realities and future needs of the growing patient population. Section 27-4 provides penalties for adulteration with sentences ranging from 5 to 21 years but laws are openly flouted. For example, storage of the drugs is required at 15-25 C [59-77 F] but, except for cold chain products, medicines are transported and stored in hot temperatures well above 30C, thus diluting their potency and efficacy.
------ Regardless of devolution of regulatory authority to provinces under the 18th Amendment, it is vital to maintain consistency with international standards, and to avoid duplication and discrepancy by provincial DRAs. Therefore, a Central Medicine Regulatory Authority [CMRA] must be constituted in Pakistan as a wholly autonomous body. The Parliament can establish an Oversight Committee to monitor the workings of the Central Medicine Regulatory Authority [CMRA]. The provincial Drug Regulatory Authorities can be mandated with the task of monitoring manufacture and sales of drugs and taking samples for lab testing from batches and the trade channels in the supply chain.
------ The CMRA should undertake a comprehensive assessment of risks and benefits profile of health products. The Central Licensing and Registration Board must be tasked with evaluating risks, benefits , effectiveness and safety of drugs before approving licenses for manufacture or import. Drugs that pose serious and imminent risk to human health must be de-registered and banned in accordance with the WHO Consolidated List of Banned Drugs. CMRA must check registration status by country, product, label, dosage, classification. It is also important to check violations of intellectual property laws. Labelling changes including additional health warnings and adverse reaction information in product monograph [packing leaflet] should be initiated by CMRA and dangerous drugs withdrawn after post-marketing studies. Strict food allergy labelling and packaging requirements must be written in the consumer protection laws to disclose full information about product safety especially for high risk groups such as paediatrics, pregnant mothers, and geriatrics.
------ The CMRA should create Supplier Rating List and track all suppliers of molecules, ingredients [including excipients] for quality standard conformance. CMRA should also conduct supplier audit and check quality of raw materials and additives to reduce risk of contamination. Suppliers of substandard materials must be blacklisted and legal action taken against spurious drug manufacturers and suppliers.
------ Among health priorities, there is no operational nation-wide pharmaco-vigilance monitoring system in Pakistan for protecting millions of patients from adverse drug reaction accidents similar to the one that happened at PIC. Presently, there is no nation-wide Public Health Programme or Adverse Drug Reaction [ADR] DataBase. Patient data records need to be systematically collected for the ADR DataBase. The Ministry of Health must urgently establish a country-wide network of Pharmaco-Vigilance Centres [PVCs] to monitor adverse reaction types and to offer emergency treatment options. Adverse Drug Summary by manufacturers must be submitted to CMRA periodically and the ADR database should be maintained for at least 25 years. On the basis of the Adverse Drug Summary the CMRA should review all such drug registrations, re-evaluate clinical trial data and ban drugs for discrepancies in efficiency and safety.
------ There is urgent need to develop an effective communication mechanism between the drug regulatory authorities, the medical profession and the patients. Currently there is no National Medicine Information Center [NMIC] to provide reliable and timely information on medicines to prescribers, patients and dispensers and run public education campaigns regularly. To deal effectively with adverse reaction fiascos and epidemics like dengue, civil society, leading health professionals and consumer rights organisations should be actively involved. Crunch Point: Next domino to fall is self-medication where patients or retail chemists [not necessarily qualified pharmacists] "self-prescribe" medications. So the consumers can dangerously overdose themselves and suffer seizures and fatal drug interactions due to drug poisoning and anaphylactic shock. To cope with such self-inflicted serious incidents, emergency toll-free hotlines need to be setup with a network of Poison Monitoring & Control Centers, fully equipped forensic labs with proper diagnostic machines and antidotes to conduct kidney, liver tests and blood cell count tests.
------ Quality Assurance Management -The Drug Quality Board should ensure company accountability through compliance with ISO standards 9001, 14001 and GMP production SOPs. The Board should examine quality control processes and quality assurance reporting and ensure real time reporting of batch data. Batch Database should be maintained by Federal and Provincial Regulatory Authorities who should monitor batch to batch deviation through root cause analysis. The Quality Board must investigate and fix responsibility for major manufacturing accidents, adverse events, and environmental errors. To efficiently control quality control operations, manufacturers should install Deviation Management System [DMS] and Quality Assurance Protocols [CAPS]. The Board should arrange training of key stakeholders such as pharmaceutical manufacturers, distributors, wholesalers, retail chemists, nursing and para-medical staff, hospital administration and Lady Health Workers [LHWs] to empower them in effective prevention of adverse-reaction disasters. Training curricula for continuing education must include core topics on pharmacovigilance and handling adverse reaction cases. The Board must install CAPA [Corrective Action and Preventive Action] system in all private/public hospitals to ensure reporting of adverse reaction cases.
------ Drug Inspectors must vigilantly take samples from each batch at the factories and from the market for testing by drug labs. During 2008-2010, 60,000 samples were sent to the drug labs for testing but only 1194 or just 2% of samples failed to meet quality standards but the results are not publicly available. Just 300 drug inspectors are responsible to check manufacturing facilities and product batches and take drug samples from the market. It is a routine practice for drug inspectors to send specimens to drug labs for testing. However, it is also a fact that sale of substandard, counterfeit, and near expiry or expired medicines continues with impunity due to laxity in law enforcement.
------ Testing of pharmaceutical raw material and excipients should also be regularly done by drug testing labs to prevent use of expired or spurious materials. Besides allopathic drugs, herbal, homeopathic and alternative medicines, food , nutritional products and cosmetics must also be brought into the regulatory net to stop companies using false or unsubstantiated claims to advertise and sell their brands. Direct-to-consumer advertising of such products that have undeclared or untested ingredients, from hair growth remedies to skin beauty creams and weight loss supplements, must be banned immediately because of potentially hazardous allergic or fatal reactions.
------ On paper, bulk purchase by state institutions is usually transparent and the approval committees 'go through the motions' of pre-qualifying the companies and short-listing the drugs before procurement. However, vested interests are deep-rooted in the institutions floating tenders. Drug companies will often go to any length to lobby and influence the committee members and influence purchase decisions. Technical members of purchase committees must, unfailingly, be of men and women of impeccable integrity drawn from outside the procuring public institutions to make absolutely certain that there is no conflict of interest involved to graft off taxpayers money.
(The writer is a business development, strategic marketing, and public-private partnership specialist with in-depth experience of both the corporate and social development sectors)