Business of Health III

In a previous blog The Business of Health I copied a paragraph from Penelope Williams’s book, Alternatives in Cancer Therapy;

The economic argument is certainly compelling. The cancer industry, indeed the entire health industry, is a tangle of vested interests including the pharmaceutical companies, the health insurance agencies, the regulatory agencies, governments, lobbyists, and professional medical associations. It would be more surprising if these organizations did not fight to protect their market, given that, for example, the chemotherapy industry alone generates about $12 to $14 billion a year in the United States alone. But to what length and whose cost?

And in a second blog about health funds made the comment:

The really frightening thing about the health fund scandal is the poor administration provided by under resourced regulators, similar to the APRA mismanagement of HIH. This is not chicken feed we’re talking about, Medibank Private turns over $2 billion and lost $175.5 million last financial year. The remaining 70% of the private health insurance market in Australia is run by over 40 other funds whose constitutions reflect the 19th Century mutual funds from which they grew. The boards of directors are responsible for taking $7 billion from contributors every year, distributing $2.4 billion in government rebates and spending $800 million in management expenses.

In this blog I seek to explore the role of clinical trials in support of conventional wisdom that only medicines approved by the TGA (or FDA) shall be subsidised under the Pharmaceutical Benefits Scheme.

The conventional wisdom about medical treatments is being challenged on two fronts. The first is that conventional ‘evidence based’ medicine relies on a rigid process of testing to determine the best treatments for a disease or medical condition. The process begins in the lab, moves through testing on animals, and culminates in what are essentially controlled experiments on people.

Medical researchers don’t use the term ‘experiments’ much, preferring the foggy euphemism of ‘clinical trials’. But one could argue that, labels notwithstanding, they are experiments, pure and simple.

In ads, when that professional looking fellow wearing a white coat and stethoscope says, “Clinical trials have proven . . .” we are programmed to accept the claim. Clinical trials say it works; it must be so. Who would deny science? As it happens, many reputable scientists. They now say that clinical trials are misused, abused, misleading, biased, and fallible.

The second is based on a premise suggested in an article in Friday’s AFR that,

modern medicine is generally practised as crisis management: wait until the diagnosis, then start treatment. But by the time symptoms of these diseases appear, damage has already been done to the body that drugs cannot address. The chronic degenerative diseases – like coronary artery disease and Alzheimer’s – have a long latency period before symptoms appear and a diagnosis is made. It follows that the majority of apparently healthy people are ‘pre-ill’. In their bodies are the seeds of the illness which will one day become overt and perhaps kill them.

Conventional drug based treatment is inappropriate for these diseases but,

There is now considerable evidence spelt out in reports from the WHO and other bodies that Type B malnutrition is a major cause of chronic degenerative diseases. If this is the case, then it is logical to treat such diseases not with drugs but with multiple micronutrient repletion, or “pharmaco-nutrition”. This can take the form of pills and capsules – “nutraceuticals”, or food formats known as “functional foods”.

This approach has been neglected hitherto because it is relatively unprofitable for drug companies – the products are hard to patent – and it is a strategy which does not sit easily with modern medical interventionism.

Over the past 100 years, the drug industry has invested huge sums in developing a range of subtle and powerful drugs to treat the many diseases we are subject to. Medical training is couched in pharmaceutical terms and this approach has provided us with an exceptional range of therapeutic tools in the treatment of disease and in acute medical emergencies.

Clinical trials come in four phases. Phase 1 trials, which are used to study agents never before used on humans, are aimed at determining the safe and tolerable dosages of very new treatments. They are not geared to demonstrate whether the treatment is effective against the target disease. In fact, cancer patients with a variety of cancers, size of tumor, and extent of metastasis are accepted into phase 1 trials; usually, though, they have all “failed therapies known to be of a benefit for their condition or have a tumor type for which no effective standard treatment regimen is currently known…”. Initially patients entering a phase 1 trial receive a relatively low dose, anticipated to be tolerable based on prior animal studies or experience in other clinical settings. After several patients have received this dose and schedule, the next cohort receive a predetermined larger dose. This process is continued until there is evidence of unacceptable toxicity at a particular dose level.

Phase 2 trials try to establish the effectiveness of a treatment or drug, administered according to a defined dose or schedule established by the phase 1 trial. Phase 3 trial compare a new treatment with the standard existing therapy. The randomised phase 3 clinical trial is the ultimate test of the clinical utility of a new drug or strategy. Patients are assigned randomly to receive either the standard therapy, the new one, or, in some cases, a placebo. A doubleblind study means that neither the patient nor the doctor knows who getting what. The assignment is usually done by computer often at a location geographically remote from where treatment is being administered. Informed consent by the patient going into a trial is particularly critical to phase trials because of the random element. Patients must sign a document attesting to their understanding of their random assignment to one or other of the treatments in the trial. The purpose of phase 4 trials is to refine the integration of the new treatment and determine its place in the primary treatment plan.

Imagine you reach that awful situation when your doctor delivers the dreaded message, “There is nothing more we can do for you. Go home and put your affairs in order.” And then he (I’ve met remarkably few oncologists; the ability to handle stress and ‘tune’ out may be one reason why women seem to be under represented in this speciality) might add: “But there is a very new drug, it’s in experimental stages still. It might help but I don’t know. It has never been used for your type of cancer; it’s being tested now. I could get you into the trial if you are interested.”

You seem to have only two choices give up, go home, and wait for the pain and dying, or go into the trial and take a longshot with debilitating, ‘unproven’ treatment. It’s unlikely that your oncologist or radiologist would tell you at this point that there are other options, that you could seek treatment outside the mainstream a treatment also ‘unproven’, also a longshot, but probably less damaging, possibly as effective. However, this is not perceived as a viable option because it has not been subjected clinical trials.

First of all, the shiny, stainless steel term ‘clinical trial’ obscures the nub of the matter. These trials are not conducted on clinics; they are conducted in clinics and on people. Whether it’s a dosage being established, or a new treatment being tried out against the old, you are the context of the trial. Your body is the testing ground, especially when you read that prospective subjects for a trial are those patients who fail other therapies.

Then you might ponder on how often the word ‘trial’ is yoked with ‘and error’. Trial and error is OK when you are doing a jigsaw puzzle, or maybe when you try out a new colour of nail polish. It’s less palatable when it’s your health, the quality of your life, and even your life itself at stake. Unfortunately, after being subjected to (some awful chemotherapy) it becomes apparent that clinical trials are not as precise as the term suggests. They rarely arrive unequivocally at a finding; or they might do so for a year or two, but then another clinical trial refutes the first finding. And another. And so on. Despite the most rigid of criteria, unknowns creep in to shift the numbers. Or the numbers are calculated in a different manner, leading to different conclusions.
( From Alternatives in Cancer Therapy by Penelope Williams – I can’t remember the publisher)

And even if the results are statistically significant, before a treatment can be used it must obtain Therapeutic Goods Administration approval. One of the cruellest things that can be done to a terminally ill patient is hold out the false hope of a cure based on a successful clinical trial. As was discussed in a recent ABC program, commercialisation of the process or treatment usually takes a minimum of 5 years and hundreds millions of dollars.

PROFESSOR DON METCALF, CELL BIOLOGIST: We have realised that it’s not much good discovering something and even patenting it. That at best will assure you of a small royalty on sales in the US.
TIM LESTER: His team’s pioneering work earned a patent now worth $5 million a year, but that’s a barely a drop in the bucket of money now paid for drugs developed overseas on the back of Metcalf’s discoveries.
PROFESSOR DON METCALF: Oh, $2 billion a year.
TIM LESTER: So why did Australia sell science that now earns the GDP of a small country?
PROFESSOR DON METCALF: It’s not stupidity, it’s not lack of foresight. It’s numbers.
TIM LESTER: No Australian company could afford to take a drug through the US approval process.
JOHN O’CONNELL: You can be looking anything from US$300 million up to US$800 million.
PETER HANSEN: It’s a crying shame that a lot of research in Australia, very, very good medical research, has managed to slip out of this country without due return or due regard to the worth or the value of that technology. It won’t happen in this case.
TIM LESTER: Not in the Monash case. In fact, not in most cases, if you believe the parade of Australian politicians and biotech promoters in Washington this week.
STEVE BRACKS, VICTORIAN PREMIER: Our ambition is to be the hub and centre of biotechnology in our region and to be amongst the top five bio-technology precincts in the world by 2010.
PROFESSOR DON METCALF: Market factors still obtain. You can develop a product in Australia, test it for clinical use, but it will still stall because to be licensed in the US it’s got to be developed and certified in the US.
TIM LESTER: The billion-dollar drug approval hurdle remains, though Australia’s emerging biotech sector will help the country hang on to discoveries longer and profit more.
JOHN O’CONNELL: A small biotech company who doesn’t have the resources or wherewithal to develop its own sales and marketing franchise around the world will look at who is the best player, who is best positioned in the specific niche my drug is in to take my drug forward and basically to get me the best economic returns.

Why is it that

“We have many palliative drugs, and many ways of suppressing the symptoms of illness, but hardly any cures. We have a wealth of epidemiological data linking dietary factors to health profiles/disease risks, and a great deal of information on mechanism: how food factors interact with our biochemistry. But almost all intervention studies with micronutrients, with the notable exception of the omega 3 fatty acids, have so far produced conflicting or negative results. In other words, our science appears to have no predictive value. Does this invalidate the science? Or are we simply asking the wrong questions?

Based on pharmaceutical thinking, most intervention studies have attempted to measure the impact of a single micronutrient on the incidence of disease. The classical approach says that if you give a compound formula to test subjects and obtain positive results, you cannot know which ingredient is exerting the benefit, so you must test each ingredient individually. But in the field of nutrition, this does not work. It is like the mechanic who, confronted with a chronically under-maintained car, insists on a test drive after changing the oil filter; another after replacing one of the spark plugs – and so on.

Each intervention on its own will hardly make enough difference to be measured. To make the car run noticeably better and last longer requires a comprehensive service. Similarly, to enable humans to live healthier and longer lives, comprehensive nutritional support is required.

In a series of web pages entitled the Pharmaceutical Drug Racket (some more of which I will refer to in later posts) a particular bit is relevant.

The Civil Abolitionist carried an article rightly titled “FDA: The American Gestapo Prosecutor or Persecutor?”, which reported that on May 6, 1992, the clinic of Jonathan Wright MD, a highly regarded nutrition specialist, was assailed by 22 armed men because the doctor had been treating his patients with safe natural substances that didn’t meet the FDA’s approval. During the SWAT type attack the front door was kicked open, guns were pointed directly at staff and the shocked patients were herded into a room. Also patient records, equipment, business records and vitamin supplies were confiscated. At the time of the article, the FDA had not as yet filed charges against Dr Wright. (70)

During last year, similar actions have taken place against three manufacturers of vitamin supplements (Allergy Research, Thorne Research and Highland Laboratories). (71)

The Nexus magazine, reporting in their Aug.-Sept. 1992 issue, writes: “This undeclared war on ‘unconventional’ medicines has been followed up with the introduction of bills in Congress which are making it difficult, if not impossible, to obtain vitamins, minerals and herbs, and which legalise their search-and-seizure techniques.” It revealed that:
“There is a bill currently pending in the House called H.R. 3642 (written and sponsored by FDA allies Representative Henry A. Waxman, and Representative John Dingell) that would:
* Make vitamins, minerals and herbs unavailable except through prescription from Medical Doctors.
* Prevent food supplements from entering the country.
* Make it illegal for anyone to sell vitamins, mineral and herbs, with a fine of up to US$1 million for each violation, plus a $250,000 against the store.
* Permit the IRS to make collections.
* Permit the FDA not only to seize but to also destroy all vitamins, minerals and herbs found on the premises.
* Permit the FDA to inspect records, embargo and recall products, and assess civil penalties for ‘serious’ violations with any judical review.

Nexus was recently contacted by an international businessman who mentioned that a bill identical in nature to the one above has been passed in the UK, that one similar was on the table in several European countries and Canada, and that one was being discussed for Australia.” (72)

In Australia, a repeal of Schedule 1, Exemptions of the Therapeutic Goods Act, scheduled for January 1994, would minimize access to natural therapy remedies by natural therapists and would threaten the existence of the natural therapy profession and manufacturers of natural therapy remedies. (73)

70. Bina Robinson (ed.), “FDA: The American gestapo protector or prosecuter?”, Civil Abolitionist, P.O. Box 26, Swain, New York 14885, vol., IV, no., 3, Summer 1992, ps 1 & 7.
71. Duncan Roads (ed.), “Alternative medicine beware”, Nexus New Times, vol. 2, no. 8, June-July 1992, p. 9.
72. Duncan Roads (ed.), “Natural medicine in the USA – a warning to Australia”, Nexus New Times, vol. 2, no. 9, Aug.-Sept. 1992, p. 9.
73. Freedom of Choice in Health Care, circular, FCHC – P.O. Box 2651, Alice Springs, NT. 0870, 1992.

So there we have the crux of the situation, ‘get me the best economic returns’. The pharmaceutical industry needs to protect it’s patents and intellectual property so that it can charge the health system ridiculously high prices to “recoup it’s R&D expenses”. Is the reliance on clinical trials the best way to discover treatments for disease or are they a cynical ploy by the business of health to ensure that the nutraceuticals or functional foods, the whole ‘pharmaco-nutrition’ approach, remains discredited, unsubsidised and under utilised ?

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2024 years ago

I only worked in research full time for a single year (after four years of training), but I’ve always maintained an interest in the area.

I think it comes down to this: what is your claim and how do you justify it?

A double blind, placebo controlled clinical trial is a methodology that attempts to minimise the inaccuracies inherent in the anecdotal accumulation of data. It is an enormously expensive process requiring thousands of people spending thousands of hours in research.

*Actually I wrote a larger reply but I wanted to double-check some claims so I might repost a much larger more comprehensive reply in a few days*

I’m not quite sure what the main point of the article is. Are you asking if mandating clinical trials for TGA approval is unfairly prejudicial to natural treatments?

Clinical trials are an exceptionally high barrier to approval. Are you suggesting we lower it? Wouldn’t that only make it more profitable for drug companies who could then avoid having to prove the efficacy of their drugs to the same degree? More thalidomide-like incidents? Or holding natural treatments to a lower standard?

If the crux of a clinical trial is the conclusion that a group subjected to one treatment derives a benefit that a group not subjected to it doesn’t, then what alternative are you proposing?

Geoff Honnor
Geoff Honnor
2024 years ago

I co-chaired a panel into HIV treatments efficacy at a Asia/Pacific HIV Network meeting in Sydney a few years ago, with Dennis Altman. One of the Australian delegates announced at the outset that she wanted to hear from some of the overseas delegates – Thailand, Phillipines, PNG etc – about their natural/traditional approaches to HIV therapy. “We make a mistake”, she averred, “in assuming that western medicine has all the answers here.”

Altman – and the overseas delegates – thought she was mildly insane. If their traditional folkloric approaches had been in any way effective, they would presumably have been at home successfully applying them. They obviously weren’t.

In Australia, we embarked on widespread compassionate access-based Phase III trials of HIV combination therapy in 1995. We also achieved fast-track approvals reforms in the ADEC/TGA/PBAC chain. Our HIV morbidity and mortality rates peaked in 1994 and have been in free-fall ever since: 753 deaths recorded following AIDS in 94, 97 recorded in 2001. Number of AIDS cases in 94 – 954; number of AIDS cases in 01 – 144.

Trial-initiated treatment turned the world upside down in HIV and created a stark and continuing difference betwen the developed, liberal democratic, health-infrastructure world and the overwhelming rest. Had we waited for things to have run the traditional evaluative course, a lot more than 8,000 Australians would have died in the meantime.

But there was – you’re absolutely right Wayne – significant risk in going there. From an ethical perspective, people for whom there are no therapeutic options other than that – or those – offering via trial, are invidiously placed. It’s absolutely incumbent on trial investigators, ethics committees and regulatory authorities to ensure that truth is told, patient safety retained as a prime objective and, importantly, that the consequences at trial clinical endpoint are adequately addressed BEFORE the trial is initiated; i.e. if someone is on the placebo arm of a randomised control trial, what happens to them on successful conclusion – or indeed unsuccessful – conclusion. We currently don’t have a national registry for all clinical trials undertaken in Australia and we should have. There’s currently no requirement for all trial outcomes to be independently reviewed and published, and there should be.

The widely prevalent belief in the mid to late 90’s that highly active antiretroviral therapy (HAART) would be able to totally eradicate HIV led to the hit hard, hit early approach. This involved throwing mind-bogglingly complex combinations at patients from initial HIV diagnosis – some people were consuming up to 35 pills a day. We now know that HAART, in it’s present incarnation, won’t eradicate HIV and we’re reaping the downside of heavy exposure to highly toxic drugs – resistance, side-effects etc. HAART has allowed HIV to become largely a chronic, manageable illness in the Australian setting but the clinical guidelines have been re-written to ensure that a more cautious approach to initiating therapy is now taken. Swings and roundabouts I guess.

I agree entirely that prevention is better than cure – the soaring cost of hypertensive therapies, lipid lowering drugs etc, etc is absolutely indicative of the need for better public health promotion. I worked with Medicines Australia (the Pharma Manufacturers’ Peak) a while back on getting them to look at their funding approaches. One radical idea that came up was for them to do something really novel like putting some funding support into the health flow well upstream of the pharmaceutical intervention point… their credit, they kind of saw the point but Australia is very much a branch office for Big Pharma and not a very profitable one.

I’ve already gone on for too long – and there’s so much more to say – but on the natural therapies front: Australians spent a cool 2 billion on complementary therapies in health year 2001-2002.
You can see that rich bronze glow of vitamin overload in the output of every sewer. I’m not sure who is being ‘denied’ here but it sure isn’t the comp therapy manufacturers….good post, mate.

2024 years ago

First of all, I’m not really making claims, merely asking questions; I expect that somebody who actually knows what they’re talking about might read the questions and supply some answers. Perhaps that person is you, Tysen?

I guess the crucial question is the last posed; “Is the reliance on clinical trials the best way to discover treatments for disease or are they a cynical ploy by the business of health to ensure that the nutraceuticals or functional foods, the whole ‘pharmaco-nutrition’ approach, remains discredited, unsubsidised and under utilised ?”

And yes, asking the question you put; “if mandating clinical trials for TGA approval is unfairly prejudicial to natural treatments?” is valid. You bolster the arguement for alternatives to double blind clinical trials by referring to thalidomide. That drug passed all the requirements of the FDA and still wreaked havoc. BTW, it seems that thalidomide is achieving something of a resurgence as a treatment for something totally separate from morning sickness; am I being too cynical in suggesting the manufacturers will stop at nothing to recoup their R&D expenses?

I guess that what I am proposing is recognition that single drug treatment; drug regimes based on testing each drug independently; subsidised medecines based exclusively on TGA approval (otherwise why have a review board?); should all be reviewed. Some cognisance should be taken of the role of traditional medicine as practised (in Australia) by the aborigines, by the Chinese, Ayurvedic treatments etc etc. And, as more evidence become available of the role played by micronutrients, eg the humble aspirin, then consideration should be given to subsidisation of neutrceuticals and functional foods.

If double blind

2024 years ago

Has anyone come up with a testing program other than the double blind test that provides a valid test of the effectiveness of a treatment.

If so noone seems to have mentioned it.

And I completely fail to see the reasoning behind it being impossible to do a double blind test of nutritional supplements or any other alternative medicine.

The problem is that no company (or even government program) will do $800 million in approval application for a treatment with $50 million in possible future profits. Whether this is because of the rarity of the disease, the competition from other treatments or the impossibility of patent protection. The only way around this is reduction in the costs of the government mandated approval process.

2024 years ago

To Woodsy

I don’t know whether my replies are written very well but I was not trying to have a go at you. Maybe it’s the particular way I phrase my sentences. Anyway, pretend Stephen Hawkin is saying them and they will take on a smooth calming monotone.

There was a very comprehensive article written on this in 1998, I think, whilst I was doing ‘Legal Issues in Medicine’ as part of my degree. I unfortunately don’t have access to Monash Law Library anymore so I can’t get a copy. I think the journal was ‘Medicine and Law’ or something like that.

The article argued that the current regulatory regime (that was largely a response to the inadequacies in the previous system that saw thalidomide approved) had gone to far. It suggested that people were dying waiting for approval of drugs that had already been approved overseas and that the whole system created a financial barrier that saw research directed to profitable drugs like Viagra rather than relatively unprofitable cancer and HIV treatments. There were a range of changes to the Therapeutic Goods Act but I can’t remember them.

I’ll try to track it down.

Geoff Honnor
Geoff Honnor
2024 years ago

There’s an interesting discussion to be had around the urgent need for harmonising approval processes across like-minded jurisdictions. NZ and Australia are working towards a single therapeutic regulatory zone while the European Union has been holding endless meetings in Brussels to go there but haven’t managed to yet.

There’s an incredible amount of time and money wasted in duplicating the selfsame medico-bureaucratic approval systems in every separate country. In reality new drug approvals generally kick off with the FDA in the US and then trickle through the other jurisdictions over the next couple of years – and 100’s of millions of bucks – later.

2024 years ago

No offence taken, Tysen. I’m so desperate for comments I’ll take them any way they come. I’d even welcome Dave Ricardo, nah…. I’m not that desperate.

The aim of the post was to stimulate debate about the health business, and all its facets. Geoff’s post in relation to HIV/AIDS is very informative (have you finished the review you were talking about Geoff) but there are many more points that could be discussed. The action by South Africa, for instance, in trying to manufacture HIV drugs under patent without paying license fees.

And why is there little prospect of an anti malarial in the forseeable future simply because most of the children that die from malaria are very poor. I.e. there is a huge market for a cheap treatment, why hasn’t some philanthropic organisation funded the development of a treatment ?

Are there readers from outside of Australia that have some ideas on how to exploit traditional medicines. India has a huge pharmaceutical market, do they obtain FDA-like approval before commercialisation of their Ayuvedic remedies. China has for decades met it’s pharmaceutical needs by copying western drugs. With their entry to WTO, will they be able to meet future demands without transgressing patent laws?

What affect will the recent Pan Pharmaceuticals fiasco have on the supplementary medicine industry? The questions are endless but we must have a go at answering some of them so that the system doesn’t become more inefficient than it already is.

2024 years ago

The most immediate effect I suspect will stem from the recent ammendments to the TGA.

A brief summary is here ->

The closing paragraph says:
“It is apparent that the Government’s intention is to move the complementary medicines and OTC industries more fully under the regulatory control of the Therapeutic Goods Administration. The legislative changes will also reinforce the public perception created by the TGA’s actions in relation to Pan that the regulator has teeth.

For the food industry, the amendments seem to indicate a stricter attitude on the part of Government to “borderline” products such as functional and novel foods which are marketed as having specific health benefits and may have implications for the on-going review in relation to health claims under the Food Standards Code. Companies “pushing the envelope” in claims made in relation to food products may well find those products declared to be therapeutic goods in the future.

While there are many amendments, this does not amount to a major overhaul of the existing system. The new regulations will oblige companies to review their advertising approval and adverse reaction notification procedures. Some new compliance procedures will be necessary. The increased penalties will also provide an incentive for many companies to update their documentation. There may be some increased compliance costs, particularly for the complementary health sector. However, these will not be substantial or onerous burdens in circumstances where mainstream media advertising was already subject to industry self-regulation.”

So it looks like the complementary health business will have to back up their claims more in line with what Penelope Williams would call “pharmaceutical thinking”.

2024 years ago

Sorry I cant remember the tag to get stuff to link and the stuff is changed when I paste it direct.

2024 years ago

I’ll try out my recently acquired HTML skills by attempting to provide the link in Tysen’s post.


Oh what a clever boy am I!!!