Time to remove the pump handle

6 minute read

Both RCTs and real world evidence are needed in the process of advancing therapeutic options for women's hormone treatments

If you do not know what the title of this article means, here is a clue … this article is written in defence of epidemiology and in recognition of a life’s work by my friend and colleague Jack Cuzick FRS, and John Snow, Professor of Epidemiology, Queen Mary University, London.

It is also in response to Professors Davis and Baber’s criticism of a recent Lancet paper written by these two researchers concerning menopausal hormone therapy (MHT), published in The Medical Republic.

The menopause societies have done a marvellous job in raising the issues around menopause to a higher level on the medical agenda. However, sometimes when one has been fighting for a long time you do not realise a friend from an enemy. Epidemiologists are not the enemy. They point clinicians to a problem so they can find a solution, and to that end, randomised controlled trials are only a part, not the whole, solution.

For example: MHT and the incidence of breast cancer. Epidemiologists had pointed out the increased incidence of breast cancer associated with taking a synthetic progestin with an oestrogen, even before the Women’s Health Initiative trial. In this RCT, where the average age of inclusion was 63 years, breast cancer was not a primary endpoint. It was a safety endpoint. This safety endpoint was crossed when the risk increased by 24%, and consequently the combination MHT arm was ceased.

This then became the “go-to” quote for MHT and breast cancer risk because it was a RCT – eight more cases of breast cancer per 10,000 women years. However, it needs to be remembered that the average age in the WHI study was 63 years.

The more important question to be answered is: “What is the risk of getting breast cancer if I take MHT between the ages of 50 and 55?”, the most common age group to use this therapy. At present the answer is we do not recommend oral oestrogen and a synthetic progestin anymore (the medication taken in the WHI trial). We believe the newer treatments are safer, for example, transdermal oestradiol and an intrauterine progestin-eluting device.

But where are the RCTs? the discerning patient may ask. The answer has to be that they don’t exist.

So around we go until there is a pivotal shift. But this shift is happening.

The 21st Century Cures Act, which was passed by the US Congress in 2016, places additional focus on the use of real world evidence data to support regulatory decision making, including approval of new indications for previously approved drugs.

The US Congress defines real world evidence as data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than traditional clinical trials. In keeping then, the recent Lancet paper, showing a clear increase in breast cancer incidence with all MHT becomes powerful evidence in shaping policy.

So what do we do?

For a start, we need to find out how to determine an individual’s increase in risk of breast cancer to titrate against benefit of MHT. GPs need more information about mammographic breast density as the evidence shows that when taking MHT an increased breast density is associated with a greater breast cancer risk.

But RCTs are very expensive.

New smaller trials with adaptive design modelling along with the collection of follow-up data gleaned from electronic case notes, have big pharmaceutical companies looking to purchase medical software companies to help develop new drugs.

This is deemed critical in the future of drug development where cost versus benefit does not align.

Let’s take a recent example of a testosterone product in women’s health. The Global Consensus Position Statement on the Use of Testosterone Therapy in Women came out recently. The position statement reads like many have done before:

There are no clearly established indications for testosterone therapy for women. Nonetheless, clinicians have treated women with testosterone for decades, with the intention of alleviating a variety of symptoms, with uncertain benefits and risks.”

And the statements always finish the same way: “The panel highlighted the pressing need for more research into testosterone therapy for women.”

 But there more than four million off-label scripts written by medical practitioners in the US for testosterone.

 So why don’t pharma companies just fix the problem and do RCTs?

Proctor and Gamble tried with the Intrinsa Patch in the early 2000s following the WHI trial. They failed, but not before sinking $US200 million. BioSante took up the cause with LibiGel and crashed after spending hundreds of millions of dollars, with the saddest thing being that the trial looking at the safety of the medication in women with higher risk of cardiovascular disease (the BLOOM trial) was never published. In this randomised controlled trial, preliminary results suggested a 30% reduction in cardiovascular events and a 25% reduction in breast cancer incidence in the active treatment arm, but as the trials looking at efficacy in sexual dysfunction failed, the results of the safety trial were never published.

And so, when an excellent review of RCTs involving the use of testosterone in women from Islam et al was published recently, it finishes with the caution about long-term safety not yet being established and warranting further investigation.

After reading the history above, what company would risk their money developing a testosterone product for women?

However, times are changing, and commonsense is prevailing.

Authorities are realising that the four million scripts written in the US are not written by crazed medicos, they are the result of their clinical experience and this can be linked to data – real world evidence of efficacy and safety. This data can be harvested and used to change the regulatory landscape.

RCTs are essential, but their design is changing, as is their cost. This year, for example, a CDK 4/6 inhibitor for male breast cancer was registered, without a large clinical trial, using very sophisticated analysis of electronic health records data. It was the first time the Food and Drug Administration had given this type of approval.

Epidemiologists are as essential in this process as are coal-face clinicians.

With scarce health dollars, surely both RCTs and real world evidence are needed in the process of advancing therapeutic options.


Dr Stephen Birrell is an adjunct academic to the Dame Roma Mitchell Research Laboratories at the Department of Medicine, University of Adelaide. He was previously the director of the Breast Cancer Unit at Flinders Medical Centre. He is a founding member of the PacRim Hormone Dependant Cancers Research Group. He is founder and chief medical officer of Havah Therapeutics and Wellend Health.

 Dr Birrell is a major shareholder in Havah Therapeutics and Wellend Health.

He has received grants and speaking honoraria from AstraZeneca Global, Pfizer, Besins Healthcare, Novartis and Roche.




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