Drug Promotion, Clinical Trials and Conflicts

“Gifts buy you time with a doc, time that might change his mind….. Money is the big resource. The pads and pens are great for access, but the dinners and what costs money. CDs, handheld computers, everything given in the name of research this is what’s thrown at docs to get them to change their minds.” A Former Detailer.

Drug industries lobbies do not appreciate people who squeal the outstanding instance is the documented case by Stanley Adams in his book Roche Versus Adams. Stanley Adams was an executive who did what he felt was right by altering the European Commission to cartelization and anti-competitive practices by Swiss based pharmaceutical giant Hoffmann-La Roche. The Commission fined Hoffmann for abuse of its dominant position in the bulk vitamin market but during antitrust proceedings disclosed information that enabled Hoffmann to identify Adams, who was consequently arrested and convicted for unauthorized disclosure under Swiss law. Roche was hounded by Swiss law, arrested while crossing the borders, and thereafter things went horribly wrong for him and his family including the suicide of his wife. Adams successfully sought damages from the Commission, which was held by the European Court to have failed its obligation “not to disclose information of kind covered by the obligations of professional secrecy, in particular information about undertakings, their business relations or their cost components.“ In 1999, Roche was fined US $ 500 Million in the US for a repeat of its offense.
A more recent instance is that of cardiologist Drugs Eric Topol. Within a week of his testifying against Merck he was deprived of his position as Chief Academic Officer at Cleveland Clinic’s Medical College. His demotion came immediately after he lambasted Merck in a videotaped testimony, in the third Vioxx (rofecoxib) lawsuit to reach trial, was too much of a coincidence. Topol has questioned Vioxx’s dafety for years and said in his testimony, played in court that he believed that Merck acted irresponsibly and committed scientific misconduct when it promoted Vioxx.

For those who want to play ball, the game starts with forms of entanglement right from the intern stage, later blossoming into cozy connections.

Forms of Entaglement

World over, and in India specifically, medicines are promoted by all means fair and foul. It is understandable, to some extent, that pharma companies aggressively market their drugs; and persuade doctors by a variety of means. But it is not clear why doctors should pretend that such marketing does not influence their prescribing behaviour and therefore it is okay not to resist the marketing overtures of drug companies.
Drug promotion is carried out by means of heavy advertising, frequent visits to private medical practitioners by the medical representatives of pharmaceutical companies with literature on their drugs, free sample of drugs, and even blatant bribes like Diaries, posters, Calendars, pens, or other gifts and sometimes also invitations to medical conferences held in five-star hotels with lavish meals and expensive give-aways. Drug companies also encourage articles in newspapers and magazines, television and radio programmes, release promotional materials as news stories about latest developments in medical field and workers and the general public to suspend their critical judgment.

Forms of entanglement: Who pays for the Pizza?

• Face to face visits from drug company representatives
• Acceptance of direct gifts of equipment, travel, or accommodation
• Acceptance of indirect gifts, through sponsorship of software of travel
• Attendance at sponsored dinners and social or recreational events
• Attendance at sponsored educational events, continuing medical education, workshops, or seminars
• Attendance at sponsored scientific conferences
• Ownership of stock or equity holdings
• Conducting sponsored research
• Company funding for medical schools, academic chairs, or lecture halls
• Membership of sponsored professional societies and associations
• Advising a sponsored disease foundation or ‘patients’ group
• Involvement with or use of sponsored clinical guidelines
• Undertaking paid consultancy work for companies
• Membership of company advisory boards of “thought leaders” or “speakers” bureau.
• Authoring “ghostwritten” scientific articles
• Medical journals’ reliance on Drug Company advertising, company purchased reprints, and sponsored supplements.

A senior professor of medicine of a prestigious Government of India post-graduate institute JIPMER, Pondicherry, in a response to a BMJ editorial, “Marketing of medicines in India : Informing, Influencing or Inducing?,” wrote : “In India and several other countries, the marketing ploys include an upgraded 5-C technique : 1. Convince by facts administered figures 2. Confuse by misrepresenting data or using junk data. 3. Coax by appealing to pragmatism: “All said and done Doctor, your patients expect you to prescribe…. 4. Corrupt and (if that fails – it does with upright Doctors even today) 5. Cry (usually a sob story of the plight of being sales executive with a target to meet or else ….) Several of my friends experience the 5-C ploy all the time, In fact we have made a video role play to sensitise our undergraduate medical students on how to face up the 5-C challenge.”

Opinions of International Panel on Drugs Advertised ion Indian edition of BMJ

• Trental 400 (pentoxifylline): The advertisement makes unsubstantiated claims of improvement in mental fiction. “(This drug id marketed only for peripheral vascular disease in America and Britain; in India it is indicated for cerebrovascular disease as well.)
• Relaxyl (diclofenac): “the claim ‘gentle’ on the gastrointestinal on tract’ is not in accord with the reported high incidence of gastrointestinal side effects (up to 30% Australian approved product information)
• Alarsin products (Indian preparation): “There is no information on active constituents, side effects, or contraindications, and the claims made are unsubstantiated.’
• Keflor (kefaclor): “Makes unsubstantiated claims such as ‘respiratory specific.”
• Fludac (Fluxetine): “This advertisement distorts the side effect profile by mentioning only the advantages it has over tricyclic antidepressants. There is no information on contraindications or dosage.”
• Globac (haemoglobin ferric ammonium citrate, copper sulphate, manganese sulphate, zinc sulphate): “No evidence for therapeutic effect is given and there are no clear indications for use.”
• Mentat (Indian preparation):” There is no information on constituents, indications, precautions, or dosage. There is no evidence given for clinical efficacy and the reference is to a study in an obscure (in house) journal.”
• Ciprodac (Ciprofloxacin): The claim ‘super power in your hands’ is meaningless. There is no mention of the generic name, constituents, contraindications, or side effects.”
• Ciprowin (Ciprofloxacin): “Makes unsubstantiated superlative claims such as ‘surgical infections: most effective and cost effective therapy’ and ‘LTRI: better than third generation cephalosporins.”
• Ciprobid (Ciprofloxacin): “The claim ‘superior to choramphenicol, aminoglycosides, cephalosporins in … bronchopneumonia, osteomyelitis’ is misleading.”

A more recent Time magazine article reportig on the No-Free Lunch campaign launched in the US had this to say: “For decades, taking gifts from drug makers has been business as usual for doctors.

The pharmaceutical industry spent $22 billion on marketing to physicians (including free samples in 2003, up from $1.2 billion in 1999, according to data from Pharmaceutical Research and Manufacturers of America (PhRMA). The industry is on track to spend almost $3 billion in 2005 solely on meeting and events for physicians, according to Verispan, a health-care market research firm in Pennsylvania. The drug industry argues, with reason, that gift giving evolved as a necessary tool for sharing if about new drugs with busy physicians who needed incentives to stop and listen.
According to Dr.Gulhati, editor of MIMS India, companies routinely spend on “educational” seminars: “Lavish but misleading events based on selective quotes from selected articles and inevitable such events are followed by lavish meals laced with alcohol. Some years back German Remedies held such society-called educational seminars all over India where the virtues of anti-hypertensive clonidine were explained in great detail. Within a month, another division of the same company held another seminar where another anti-hypertensive Xipamid was placed at the Top-selling while clonidine was at Number 10 the bottom!” In India, medical association journals lend themselves to include special advertisement supplements, which in effect turn out to be a marketing outlet for a particular drug or class of drugs of a drug company. However in India advertisement in journals is a relatively low source of influence and persuasion compared to gifting and related inducements and of course part or full sponsorship of seminar events and the creation and recruitment of pliable creatures called KOLs, which we discuss below.

Doctors as KOLs: “Magic Realists” of the Medical World.
Key Opinion Leaders (KOLs) are influential specialists in their fields such as doctors at teaching hospitals, senior consultants, authors, etc. An endorsement by a KOL in favour of new products or new uses of old products is a Top-selling priority for pharma companies. Aggressive, often highly unethical, tools are employed to capture KOLs, consider the following actions of drug companies and their KOLs:

• Such pharmaceuticals sponsored over a dozen “educational seminars” all over India to advocate its use in infertile women. KOLs were paid up to Rs.30,000 per lecture to endorse the new indicating. It is illegal to promote any drug for unapproved indications.”
• According to one “Key Opinion Leader” of Jammu, he has already prescribed cisapride to 40,000patients. Furthermore, he prescribes cisapride to 150 patients every week. Another KOL from Jammu says the same thing in the same language and he too has prescribed for 40,000 patients and from 1990 at that when the drug was not even marketed! Another KOL says it is okay to give it to infants for pain in abdomen when it is prohibited for use in children and yet another has determined that side-effects of cisapride are to be found in 0.0001% of the patients whereas the USFDA says it is 5 percent! With such KOLs as doctors who needs enemies!
• Most Indian medical journals would have non-specific vague quotes from doctors testifying to the supposed efficacy of a drug.
• In return professional associations endorse products for instance, the Delhi branch of the Indian Medical Association endorsed nimesulide and in its society-called survey for the purpose, the sample of adults to children taken if extrapolated results in the number of children of India being more than the population of India.
• The Journal of Indian Medical Association (JIMA) has a “Research Analysis Section” that in effect provides a platform to Pharma companies to market their products. Example: JIMA (Volume 99, No3 July-Sep 2001) published two articles in a span of a few months, both promoting iron polymaltose preparations claiming superiority of IP over Ferrous fumerate and then quotes the publication of these papers in marketing Mumfer, its brand of IP!

Cozy Connections with Professional Associations

We look at some examples of the cozy connections between Professional; Associations and the drug industry patients may be alarmed that their prescribers, with a few honourable exceptions, can get swayed society easily. Drug companies sponsor conferences and here are some examples:

• The Indian Medical Association requested major drug companies to become “Principal Sponsor” of its All India Conference by paying whopping Rs.75 lacs. The company could also become “Full day Sponsor” by paying Rs.25 lacs. Fund were sought to feed the participation at the rate of Rs.10 lacs for each lunch and Rs.15 lacs for the banquet.
• Indian college of Interventional Cardiology asked for Rs.5 lacs for placing a banner in the main hall.
• Indian Society of Critical Care Medicine sought Rs.15 lacs for “Principal Sponsor”, Rs.15 lacs for each lunch and and Rs.10 lacs for banquet.
• The Maharasthra Branch of the Indian Society of Anesthesiologists sought Rs.500,000 to designate a company as the “Main Sponsor of the Conference”.
• The Indian Orthopaedic Association asked Rs.10 lacs from a company towards “Sponsorship of the Main Hall” whatever it means. For each meal the companies were asked to pay Rs.8 lacs.
• National College of Chest Physicians/Indian Chest Society sought Rs.15 lacs for three lunches and 17 lacs for dinners for its conference in Ahmedabad.
• Indian Association of Surgical Oncology wanted Rs.4 lacs from any company that wanted to become “Principal Sponsor”.
• Indian Association of Cardiovascular-Thoracic surgeons sought Rs.1 lac to give an opportunity to any company to introduce its product in 7 minutes.
• Indian Clinical Epidemiological Network that held a conference in Agra sought Rs.1,00,000 to take participants from Delhi to Agra “for augmenting Quality of Hospitality.” Another Rs.1,00,000 were sought to serve “A Glass of Beer/Wine during Dinners and Banquets
• Three companies namely Organon (India) Ltd, Indo-French Marketing Company and Universal Biomedics were the principal financiers of National Association of Sexology Conference.
• Top-selling British cardiologists can collect more than $8,700, for an hour of lecturing to colleges, and they also may be paid for from putting their names that review drugs in medical journals, according to a report by members of the British House of Commons in April 2005.
• There is always a “close bondage between the medical profession and pharmaceutical industries” wrote Organizing Secretary of the Cardiological Society of India seeking funds from the drug companies.
• Financial support from industries is mandatory to make Annual Conference of Cardio Vascular Thoracic Surgeons successful” – Organising Secretary.
• The Sponsorship of the Clock Room will be Rs.1 lac while balloons will cost Rs.1 lacs each.” Organising Secretary, National Conference on Pulmonary Diseases.
• An article on a product of interest to your company in the Souvenir can be published on payment of Rs.1 lac.” – Editor , Souvenior of All India Medical Conference.

How Drug Industry Influences Doctor’s Prescription

….. The temptations offered by the drug industry are too irresistible to be turned a blind eye to. Doctors, Doctors, however, argue that they are not gullible enough to be influenced by glib talks and gifts. Unfortunately this is a self-illusion. The Forum for Medical Ethics, Mumbai, in its recent survey asked doctors if going on a drug company sponsored cruise would affect their prescriptions towards the company’s products, the overwhelming said No. But most said yes, when asked if a sponsored cruise influenced the prescription practice of at least one doctor they knew. Indeed doctors who frequently see drug representatives are more willing to prescribe new drugs, are more likely to write a drug that is clinically not indicated, and to don not like ending consultations with advice only. After the cosy relationship between doctors and medical representatives does not escape patients’ discerning eyes.
“As drugs” Anand aptly puts it, “No one should have any doubt that the costs of industry sponsored trips, gifts conferences and symposia are simply added to the prices of drugs and devices. Drug industry treats doctors as prescribers and not cares givers. When we attend a sponsored banquet, we may be adding significantly to the drugs prices in India.”

“Doctors everywhere love freebies”

On drugs. M.K. Mani wrote of one conference, “We can easily afford to buy an odd pen or a briefcase, a flask or a shopping bag. Yet no sooner did some company announce on the very loud audio system that there were some goodies available at some stall, a log queue would form there leaving the speaker to cast his wisdom on empty chairs. Do we need to demean ourselves to this extent? Should we allow commercial interests to dominate us to society completely?” Richard Smith reinforces this further, “That healthcare professional can be bought for a self adhesive memo pad, pen, coffee mug, or pizza is pathetic Are we society poor that we cannot buy our own pen, note pad or lunch?”

What is to be Done?

Thirty years ago, medicines policy was a technical discourse mainly among UN agencies, ministries of health, and international experts. However, the growing AIDS pandemic has galvanized discussions about access to treatment. The United Nations, donors, recipient governments and suppliers are being pressured by a growing global network of public interest NGOs and Civil society groups that need medicines and are not able to get them. New bodies, such as the GFATM, have been founded to provide financing for national programs to tackle three of the major diseases of poverty. Existing organizations, both public and private, have become increasingly engaged in finding new ways to increase access to medicines. But more needs to be done, and it will require new thinking and new approaches.

In the last decade, most developing countries have undertaken measures to improve access to medicines, with varying degrees of success. Even where there have been setbacks, the experience gained strongly indicates that progress is possible. Where both initiatives and the results have been monitored, lessons emerge that can be adapted to local conditions and applied elsewhere. A key finding is the need to involve the community in developing health policies and programming.
– UN Millennium Project, 2005. Prescription for Healthy Development: Increasing Access to Medicines

There are 2 analogies I want to leave you with to illustrate the unreasonableness of CDERs standard of evidence as applied to safety, both pre-and post –approval. If the weather-man says there is an 80% chance of rain, most people would bring an umbrella. Using CDERS standard, you wouldn’t the bring an umbrella until there was a 95% or greater chance of rain. The second analogy is more graphic, but I think it brings home the point more clearly. Imagine for a moment that you have a pistol with a barrel having 100 chambers. Now, randomly lace 95 bullets into those chambers. The Gun represents a drug and the bullets represent a serious safety problem. Using CDERs standard, only when you have 95 bullets or more in the gun will you agree that the gun is loaded and a safety problem exists. Lets remove 5 bullets at random. We know have 90 bullets distributed across 100 chambers. Because there is only a 90% chance that a bullet will fire when I pull the trigger, CDER would conclude that the gun is not loaded and that the drug is safe.
– Drugs. David J. Graham, MD, MPH, Testimony before US senate Committee, November 18, 2004.

In this book we have surveyed, within the limits of space, factors that have and will impinge on drug availability in India. The situation is quite dismal in terms of availability of medicines for the poor and in terms of access to health care, and there are enormous concerns of safety and rationality of the drugs available in India.
In the coming years, issue of access to drugs, highlighted by lack of access to drugs for TB, malaria, HIV AIDS and a host of communicable and non- communicable diseases, are likely to gain prominence. Closely related are regulation of drug-pricing and drug patent issue n newly emerging drugs on diseases of public health importance. An area of concern would be the mindless enlargement of a vaccine-for-every disease policy rather than at the root causes of ill-health: typified by “let us have diarrhea vaccine if we cannot provide clean drinking water”. Therapeutic and populist fashions seem to dictate health policies than evidence-based risk/benefit analysis.

The other worry is the lack of safeguards in clinical trials even as India becomes a destination for contract research and clinical outsourcing.
Indeed a situation of poverty and chaos amidst booming pharma scrips and international businesses.

What then needs to be done? A minimum wish list would include:
• Recognize access to medicines and health as a human rights issue.
• Incorporate explicitly gender concerns in pharma policy making and marketing of drugs.
• Restricting drugs available in India to essential drugs as per the government’s own NEML (2003) or the 14th Model List of Essential Medicines (March 2005) of the WHO.
• A comprehensive Rational Drug Policy that includes no unnecessary formulations presentations in terms of syrups, capsules and injections a vaccine policy strictly guided by science of public health and prioritization of use of public money; a limited list of over the counter drugs to be available.
• Promotion of drugs under only generic names with strict regulation of promotional activities of drug companies; strict guidelines of sponsorship, if at all, of symposia and other scientific meetings.
• Mandatory disclosure of funding and potential conflict of interests in all clinical trials, medical research and publications and also by policy makers and members in various government committees related to pharmaceutical and health.
• A limit on cross-practice: compulsory continuing medical education of doctors; improvement in medical education, as well as medical education fee regulation; a systematic policy of research on non-allopathic drugs as well as a pricing an marketing policy for non-allopathic drugs.
• Weeding out all irrational an harmful medicines
• Price control on all essential drugs marketed in India
• Introduction of Essential drug Lists and Standard Treatment Guidelines in especially health facilities of the governments at the Center and State followed by legal changes to enable production and marketing of only essential drugs in India (that is both private and public sectors).
• Access to objective information on drug risks and hazards from the Drugs Controller General of India.
• Transparent Pooled procurement in all States as in Tamil Nadu and Delhi State Government after assessing rational, essential drug needs (which has resulted in procurement of drugs for the public health facilities at a rate which is up to 2% of the prices in the retail market!).
• Implementing the Mashelkar Committee recommendations without centralization and bureaucratization.
• Action on corruption at all levels of drug administration including in the drug industry.
• No product patents on diseases of the national programme and more careful orchestration of the health needs of India.
• Increasing the ease of getting/issuing compulsory licensing of drugs of interests of the people of India.
• Transparent access to information on clinical trials with a clinical registry accessible in the public domain.
• Specific research on gender related aspects of medicines access and use by women and girls and men and boys.
• Universal Health Access and Insurance for every citizen of India by increasing the government’s per capita expenditure on health and recognizing user fees is a deterrent to access to health and medicines.
The need for consumer action cannot be over-emphasized in view of the aggressive and unethical marketing practices employed by the pharmaceutical companies. Consumer awareness is an important pre-requisite for consumer action. Consumers, individually or as a group, can play a key role in protecting themselves and preventing unethical promotion of drugs, and unnecessary suffering caused by dangerous drugs or by irrational use of drugs.
Prescribers in turn can facilitate patient compliance of drugs by doing several things. For an illustrative list, see box below.
Individual consumer action may be taken by:
• Having basic knowledge of medicines and how they work
• Knowing which drugs are hazardous, banned or need to be avoided.
• Avoiding taking drugs, which are useless or irrational
• Asking your doctor to prescribe drugs by their generic names and avoiding OTC drugs whenever possible.
• Asking your doctor for more information on the drug you have been prescribed
• Avoiding tonics and other health restoratives; instead ensuring a balanced diet for the whole family.
• Participating in activities of local consumer groups and drug action networks.
• Critically evaluating advertisements for health products.
• Reporting any unethical promotion of drugs to the local health or consumer group.

Aids to Improving Patient Adherence to Treatment

Patient Leaflets.

Patient leaflets reinforce the information given by the prescriber and pharmacist. The text should be clear, common language and in easily legible print.

Pictorials and short descriptions

If the patient cannot read, try pictorials. It they are not available, make pictorials or short descriptions for your P-drugs, and photocopy them.

Day Calendar

A day calendar indicates which drug should be taken at different times of the day. It can be use words or pictorials: a low sun on the left for morning, a high sun for midday, a sinking sun fir the end of the day and a moon for the night.

Drug passport

A small book or leaflet with an overview of the different drugs that the patient is using, including recommended dosage.

Dosage box

The dosage box is becoming popular in industrialized countries. It is especially helpful when many different drugs are used at different times during the day. The box has compartments for the different times per day (usually four), spread over seven days. It can then be refilled each week. If cost is a problem, the box can be made locally from cardboard. In tropical countries a cool and clean place to store the box will be necessary.

Even if the patient aids described her do not exist in your country, with creativity you can often find your own solutions. The important thing is to give your patient the information and tools they need to use drugs appropriately.
Source: Guide to Good Prescribing. WHO Action Programme on essential drugs, Geneva, 1995.

Group consumer action is more effective in bringing about necessary changes. It would require getting together like-minded people who are genuinely concerned about the issues. Groups may be formal or informal. Informal groups may be formed where people simply come together on single issues requiring urgent steps for redressal. Formal groups may be formed with a proper structure as per the rules of a society or trust with Board of Trustees. It may be registered as such.

Some of the activities groups can undertake are:
• Create awareness of health issues and disseminate information
• Bring out regular publications to keep consumers aware
• Organise and encourage people to participate in health activities
• Identify publications essential for drug information
• Ensure availability of preventive health amenities and services such as clean water, sanitation, immunization an healthy environment in your neighbourhood, and safe working conditions at work place
• Report all drug shortages to the Drug Controller of India
• Participate in health and consumer campaigns
• Write in local press and publicise issues of concern.

Some all-India networks / groups/resource persons that can be consulted by consumer groups are the All India Drug Action Network: Bulletin of Drug Health information (BODHI) (email: fha@cal.vsnl.net.in ; the MedicoFriend Circle www. Mfcindia.org ; the an Swasthya Abhiyan (JSA) http://phm-india.org ; Affordable Medicines & Treatment Campaign http://www.lawyerscollective.org / lc_hivaids/amtc ; and Indian journal of Medical Ethics http://www.isuesinmedicalethics.org ; LOCOST, the publishers of this book http://www.locostindia.com

End notes

1. Report of the Task Force on HIV/AIDS, Malaria, TB and Access to Essential drugs Medicines, Working group on Essential drugs Medicines Sterling Va.: Earthscan.
2. The Hepatitis B vaccine and related scare mongering is an example. See “Why we do not need to give Hepatitis B vaccine for all newborns: Letter to Health Minister,” mfc bulletin, 313-314, Oct 05 – Jan06.
3. Some of the formulations are after Phadke, Anant. Drug supply and Use: Towards a Rational Drug Policy in India. New Delhi: Sage Publications, 1998.
4. The UN Millennium Project, 2005, report Prescription for Healthy Development: Increasing Access to Medicines. (Report of the Task Force on HIV/AIDS, Malaria, TB and Access to Essential Medicines, Working Group on Access to Essential Medicines, Sterling, VaL Earthscan) has this to say in its recommendations related to gender:

Nationally:

• Ensure women have access to accurate, gender-sensitive medicines information.
• Promote innovative and outcome-based research in the gendered aspects of medicines access and use by women and girls and men and boys.
• Collect sex-and gender-disaggregated data on access and use, which, in combination with adequate gender analysis, should inform policies, plans and budgets.
• Ensure that women and girls have equal access to medicines.

• Ensure full and equitable access to sexual and reproductive health services and commodities.
• Ensure that national essential medicines lists contain the core medicines and devices for sexual and reproductive health recommended by the UNFPA and WHO.