DRUG SECRECY:HELP US FIGHT FOR GREATER OPENNESS

Drug companies enjoy greater secrecy under law than any other industry group.

They do not even have to divulge the side effects of a new drug.

For 49 issues, WDDTY has been warning of the side effects of drugs and treatments. For this, our 50th issue, we say it’s time for the drugs industry and governments around the world to guarantee responsible and accountable medicine.

The drugs industry has grown in this century to become one of the biggest on earth, while enjoying a level of secrecy that is unreasonable and that goes far beyond the bounds needed to maintain commercial confidences. In Britain, a Crown servant who reveals confidential information about a drug company or its research can be jailed for two years.

This secrecy costs lives. Drugs can cure; they can also do damage or even kill, especially when they are new and inadequately tested. It is an unavoidable fact that a handful of people can suffer serious side effects when they are prescribed a drug that’s the only way, brutal though it is, that medicine can find out if a new treatment’s risks outweigh its benefits.

Our concern is that people are being harmed unnecessarily every day. This is the price we are paying for secrecy, a conspiracy between government, the drugs industry and some doctors. Of the three, the doctor is probably the least culpable he’s the look out while the big boys raid the bank.

Our charge against government and the drugs industry is that:

l they can withhold vital evidence about the dangers of drugs,

l they do not always properly research new drugs when they come on to the market. Some trials are falsified,

l in Britain, they do not reveal the reasoning behind the granting of a licence to a drug.

Our charge against doctors is that:

l some are too ready to test a new drug for financial gain, sometimes inappropriately.

In Britain, some of these issues were addressed in the Medicines Information Bill, which was blocked in 1993 by a government that seemed not to want greater openness. To understand this secrecy, we must first understand the way the industry works, often in liaison with government. Much of what follows is particular to Britain one of the most secret of societies but there are lessons here from which every country can learn.

If you agree with us that these conditions are intolerable, sign the petition form we’ve enclosed with this issue and get as many of your friends and relatives to sign it as well. Then return the signed form to us. If we have enough support among our subscribers to end drug secrecy, we will formally present all the petitions we’ve gathered to the government.

The thalidomide drug scandal of the early 1960s shocked the world. Images of babies deformed by a drug that was supposedly safe for mother and child were bad enough; worse was to follow when it was discovered that the pharmaceutical company concerned had evidence of the possible risk before it released the drug.

It also sparked the beginnings of consumer concern about an industry that had previously been taken on trust. In America, it led to more openness; the Food and Drug Administration (FDA) eventually started to publish its deliberations and reasons for granting a licence to a drug, and it has been estimated that 13 million Americans buy the weighty Physicians’ Drug Reference, which lists all the known risks of drugs. Package inserts are also made available with most drugs.

America was 10 years ahead of Britain in introducing drug control legislation; it had introduced some basic drug laws, the Food and Drug Act of 1938, which were sufficient to keep out thalidomide. Nonetheless, the Kefauver Harris amendment to the act in 1962 gave the FDA powers to obtain satisfactory evidence of drug efficacy and safety before a licence for sale was granted.

Britain’s approach was more cautious and far slower. In 1963, it introduced the yellow card system, devised by Dr Bill Inman, who went on to set up the Drug Safety Research Unit in Southampton in 1980, the largest independent evaluator of drug side effects in the UK.

The yellow card system, which asks GPs to voluntarily complete details of side effects of new drugs, has never been a total success. Even Professor Inman does not know the take up rate, but it is estimated that no more than 15 per cent of doctors complete the cards, and that number is falling. Professor Inman has noted, though, that fewer doctors complete the yellow cards when there is a competing side effects trial being run by the drug company concerned, and for which the doctor is paid.

In 1968, Britain introduced the Medicines Act to regulate the introduction of new drugs. The Medicines Commission was established a year later, and its task was to approve new drugs until it was replaced by the Medicines Control Agency in 1988; the Committee on Safety of Medicines, which controls all drugs once on the market, was set-up in 1970, followed in 1975 by the Committee on the Review of Medicines.

To prove its safety, quality and efficacy, a drug has to pass through several stages before a licence to market is granted. The first stage usually involves animal testing a highly unreliable test in any event which gives a crude indication of therapeutic effects and dosage; the second is an early study on healthy human volunteers to more accurately assess dosage; the third is the most exhaustive and expensive and involves clinical trials.

Sometimes a trial tests the new drug against a placebo, but there are no set guidelines. A test group has been as small as 18 people, but usually is about 1500 strong. This is a remarkably low number compared to the tens of thousands unwittingly testing the drug, once it has received a licence.

For obvious reasons, it is also rare for a clinical trial to include children, pregnant women and the elderly the very people who may suffer side effects once the drug is on the market and there is no specified time to assess the longer term effects of the drug. Some tests are aborted early if the responses seem particularly favourable, as happened with the anti-AIDS drug AZT, later discredited in the Concorde tests (see p 4).

By this stage, there is immense pressure on the drug company to produce a successful trial. The drug may have been researched and developed for 10 years, costing the company as much as £150m. Fraudulent research or incomplete data has been reported, and even the British Medical Journal has published a book on the subject, Fraud and Misconduct in Medical Research.

The FDA has discovered “serious deficiencies” in 11 per cent of clinical trials in the US. In the UK, the anti-arthritis drug Opren had only one clinical trial among the over 65s, and no tests were done to assess how different doses work in different age groups. Despite this, a licence was granted in the UK, whereas the FDA waited for further tests. Over 4000 Britons, many elderly, contacted the Opren Action Group alleging some injury, mainly persistent increased sensitivity to light, and a further 100 were reported to have died.

Deficiency is one thing, fraud another. While the level of fraud in clinical trials is not known in the UK, it is reckoned that “a small but significant amount of data . . . is fraudulent,” according to Dr Frank Wells, medical director of the Association of the British Pharmaceutical Industry (ABPI). However, Dr Vernon Coleman, one of medicine’s greatest scourges, states: “It is now reliably estimated that at least 12 per cent of scientific research is fraudulent” (Betrayal of Trust, European Medical Journal 1994).

The high costs of research tend to prevent highly experimental work. Most drugs are “me too” products. In one 1981 study by Dr John Griffin, then a senior official in the medicines division at the Department of Health, it was discovered that the 204 new chemical entities (NCEs) marketed over the previous decade had largely been introduced into areas “already heavily oversubscribed”, he said. “Innovation is directed towards commercial returns rather than therapeutic need.”

Once a drug has been licensed, the drug company has only one legal requirement in Britain: to advertise the drug name, licence number and manufacturer details in an obscure official journal called the London Gazette. In the US, the FDA prints chapter and verse its reasons for granting the licence; in the case of the antidepressant Prozac, for example, its reasons fill 48 pages, which are freely available.

Under the Freedom of Information Act in the US, the FDA can disclose over 90 per cent of its records. Ironically, 85 per cent of requests for information come from the pharmaceutical industry, which opposes similar access in the UK.

In the UK, the deliberations of the UK’s Medicines Control Agency are kept secret, and no government minister or official can publish any information it finds out about a drug company or its research. Any breach of this law can result in two years’ imprisonment.

This extraordinary state of affairs, the most extreme protection enjoyed by any industry group, is enshrined in Section 118 of the 1968 Medicines Act, a section originally designed to protect commercial secrets, but which is used as a blanket ban on all information, including that which the public should have a right to know. It “protects” the public from knowing about adverse drug reactions (ADRs), deaths caused by the drug, or even the types of drugs, good or bad, used by the National Health Service, and the cost to the taxpayer.

Once the drug has received a licence, its sales teams move into top gear. Stories are legion of the paid holiday abroad or the gift of the personal computer to encourage GPs to prescribe the new drug, although these practices have in the main now been discredited. It’s worth noting that despite the pre marketing trials, the true risks of a drug aren’t fully understood. This was best put by Sir William Asscher, former chairman of the Committee on Safety of Medicines, in a private meeting when he said: “. . . by the time a drug is licensed we really know very little in the case of a new chemical entity about its possible risks.”

Despite this knowledge gap, the Medicines Control Agency prides itself on being the fastest regulator in Europe granting a licence on average within 70 days so making Britons the world’s guinea pigs.

A number of drugs are also granted licences in the UK while being rejected or delayed licence in the US. One example of this was the drug Centoxin, created by its US manufacturer Centocor to treat blood poisoning. The FDA had refused it a licence, but one had been granted in the UK in May 1991. It was suddenly withdrawn in January 1993 when further studies from the US had shown “excess mortality” among patients who did not have the right type of blood poisoning. By the time this discovery was made, 2000 Britons had taken the drug, although no deaths had been reported at the time.

The final requirement under the Act is for the drug to undergo a post marketing surveillance study to monitor side effects. This area has been subject to the greatest abuse, and has been described by Professor Inman of the Drug Safety Research Unit as marketing dressed up as research. Patients unwittingly have been switched from a safer, effective course of treatment to a new drug so the doctor can claim his gift or financial reward. Amounts earned vary; Dr Vernon Coleman reckons doctors can earn an additional £50,000 a year by prescribing the new drugs to large numbers of patients; the British Medical Association says the agreed sum per report is £7, although there can be 10 report cards per patient.

“I blew the whistle on one product where a doctor had 230 patients in a study for rheumatoid arthritis when he had only five sufferers in his practice. He alone was responsible for 10 per cent of the entire market for that drug,” Professor Inman told WDDTY. He carried out a survey among 28,402 GPs in Britain and discovered that just 10 per cent of GPs are responsible for creating 42 per cent of a new drug’s total market, so putting at risk their patients when the drug’s side effects are not properly known (BMJ, 11 September, 1993).

A report by the Medicines Control Agency in 1992 revealed that 31 post marketing trials were inadequate, biased and poorly designed (BMJ, 1992;204:1470-2).

In America, the FDA has set up MEDWatch to encourage health professionals to report side effects. Currently, it estimates that only 1 per cent of side effects are reported to the FDA (JAMA, 2 June 1993).

One of Professor Inman’s greatest successes, achieved shortly before he retired in 1993, was to have included in a code of practice to all doctors the stipulation that no treatment should be changed just so that a patient can be included in a study of a new drug. Nonetheless, it is just a guide, and there is no compulsion to adhere to it.

The most scandalous aspect of the post marketing study is that the drug company is not obligated to publish the research; it must inform the drugs authorities but, under Section 118, need not reveal it to the public. This means that a drug company and a drug authority can be aware of a serious side effect, even though a GP is still prescribing it. He, of course, would be as ignorant of the findings as the patient.

Fortunately, in two recent cases, the pharmaceutical company has acted responsibly when further tests have shown a possible side effect not picked up by the limited clinical trials. In April 1993, Boots withdrew its 100mg Manoplax tablets, licensed the previous September to treat congestive heart failure. Tests in the US, Canada and Scandinavia found patients were more likely to die of heart failure at that dosage than without it. About 900 patients received the drug at the more dangerous dosage level.

In June 1992 the antibiotic Teflox was withdrawn in the UK after 20,000 patients had been given it in just eight months. The US manufacturer Abbott Laboratories discovered the drug could cause liver and kidney problems, and a life threatening shock reaction.

Section 118 of the Medicines Act has also prevented an explanation of why the tranquillizer Halcion was withdrawn at 24 hours notice in 1991, or why two of the three vaccines for the measles mumps rubella (MMR) shot were withdrawn after a £20m government promotion.

It sometimes happens that only when side effects are reported by the media, or discovered by an independent research group are the dangers of a drug known. For example, nobody knows how many people a year die as a direct result of drugs treatment.

Global figures are released by the Committee on Safety of Medicines, but they are not itemized to specific drugs. For instance, it revealed that 280 people died from taking prescribed drugs in 1987, yet the Medical Research Council estimates that 600 people die each year in the UK from taking non-steroidal anti-inflammatory drugs alone. However, Professor Michael Rawlins, the new chairman of the CSM, estimates that only 10 per cent of all serious adverse reactions are ever reported to the authority.

It has been estimated by drugs expert Dr Joe Collier that 100 people could die if a new drug with an unknown, lethal adverse reaction were prescribed to 30,000 patients.

A change to this unsatisfactory state of affairs was attempted in 1993 by a private member’s bill, introduced by Labour MP Giles Radice, and supported by the National Consumer Council, the Campaign for Freedom of Information and by Social Audit. The Medicines Information Bill endeavoured to repeal Section 118, a measure which seemed to have support from all parties, from consumer organizations and even from Professor Asscher. Despite this, it was eventually blocked by the government and the drugs industry.

Instead, the government offered a sop for wrecking the bill, said Charles Medawar of Social Audit. The UK government offered to play a role in opening up the reporting of medicine in the EC, which he described as “laughable, bearing in mind the British government’s record”. Already, Denmark, France, Greece and The Netherlands have a more open reporting process on drugs than Britain. It also offered a voluntary code of disclosure, following discussions with the ABPI. The draft proposals are “not worth the paper they’re written on,” said Medawar.

A more open climate is being created in Britain by EC regulations. Since January, all drugs were supposed to come with packet inserts outlining side effects, although the government is attempting to have generic drugs removed from this requirement. Apparently, the information on the package inserts is more comprehensive than that supplied to GPs, although a 1990 survey showed that only a quarter of British doctors ever read the Data Sheet Compendium anyway, and most threw away the updates unread.

In 1995, the European Medicines Evaluation Agency opens its doors in London and will begin to replace the British regulatory system, although there will be a dual procedure for some time. It remains to be seen just how open the new agency will be.

Any change should be an improvement on the British secret system. As it stands, it is a very long way away from the World Health Organization’s statement of 1983 which said: “. . . science and technology can contribute to the improvement of health standards only if the people themselves become full partners of the health care providers in safeguarding and promoting health . . . people have not only the right to participate individually and collectively in the planning and implementation of health care programmes, but also a duty to do so.”

!ABryan Hubbard