Genetic analysis "replacing" clinical trials?

AlaskaAngel

I'm fond of the idea of using genetics as more efficient way to find "the cures", but the devil is in the details and I don't quite understand the "how" of it. Here is one example... but.... it still relies on the use of the clinical trials it is supposed to replace....

http://www.fiercebiotech.com/story/abbott-aids-biotech-epizyme-matching-epigenetic-drug-cancer-patients/2013-04-18

"

As with most such pacts, Celgene will pay the bulk of potential money to Epizyme based on success in clinical trials and beyond.

AlaskaAngel

This article provides some explanation of how genetic analysis would work. The article uses the HER2 positive patients as one example, and admits that identification for that is more complicated than just testing genetically positive for HER2, since the targeting drug developed for HER2 positivity doesn't work for 100% of those who are HER2 positive, and even when it does work, it eventually stops working for some portion of those treated. In addition (although the article doesn't mention it) some patients who test genetically positive for HER2 do just fine without the targeting drug--and those patients take the very expensive drug (which can have significant side effects) anyway "just in case" because at present there isn't a way to tell which patients benefit and which ones don't need it. In addition, at present they also take spendy and difficult course of standard chemotherapy "just in case". That has been the history of the genetically targeted drug for over 5 years now. A newer sort of version of it is out... but as yet is not being given to the newly diagnosed.

http://discovermagazine.com/2012/nov/08-your-cancer-your-cure-how-new-genetic-tests-saving-lives 

August 20, 2012 article about replacing the randomized clinical trials. What the process is exactly for replacing them with something better wasn't clear to me:

http://www.medscape.com/viewarticle/768635 

Somehow there is a disconnection here for me. There are people out there in the "developing world" who don't understand the basis for established inoculations, and yet the medical world is going to connect them to the proposed sophisticated technology in a way that is meaningful for them???

http://www.medcrunch.net/medcrunch-interview-eric-topol-md/ 

"Franz Wiesbauer:  Do you really think that it’s an actual democratization I mean thinking of the fact that it can still be complicated to use those devices, don’t you think that these devices and the technology will kind of select the more intelligent folks, the more intelligent patients and when we’re talking about this new type of medicine, are we talking about a type of medicine that’s only accessible to the smartest or the richest?  What do you think?

Eric Topol:  Well, I mean there is an issue there.  We have a digital divide so we’re going to have a digital medical divide too unfortunately and I write about that in the book too.  I think this is an issue which we have to deal with but if we can come up with better ways to prevent diseases in the future then it should hopefully effect all individuals and also one of the most important things you know, just last week, this min i-in device which is a USB sized device and it can sequence genomes in minutes.  It can be done anywhere in the world just like all these sensors, anywhere in the world, in the developing world, just as it can be in the developed world.  So, we see a flat Earth story here.  This is really something that is applicable across the board to all people and so there is of course, a limitation of this because there is a lack of access, for example just broad band access, no less medical access so that’s something that just has to be worked on over time.  It’s a key issue to promote health care worldwide."

AlaskaAngel

There is humor about all this. Here is a great example of the present state of technology through non-human transcription of a human discussion about technology...  (Next, let's just apply the technology to matching drugs with genetic profiles....!)

http://www.fronterasdesk.org/audioclips/13477/ 

And an interesting example of non-human interpretation of CBS news about Amelia Earhart (read the video transcript):

http://www.cbsnews.com/video/watch/?id=50147979n 

AlaskaAngel

Here's one that is vague but a bit better at describing the process, although..... "finding out what happens" does not automatically equate to "success". If you have 2 patients with a genetic profile for whom it "works", but it doesn't work for most people with the selected gene, do you scrap the drug or have it manufactured and distributed for those 2 people?

 

http://www.medicalprogresstoday.com/2012/09/eric-topol-lets-get-rid-of-randomized-controlled-trials.php

"If you're a cancer researcher, the first thing you want to know is how many other cancers overexpress CD30? It turns out, according to Xconomy, that researchers at MD Anderson and Stanford started looking at Adcetris as a treatment for a disease that wasn't even on Seattle Genetics radar screen, cutaneous T-cell lymphoma (CTCL). If researchers get a hit, and they did, Seattle Genetics can then turn around and run a larger trial to confirm the benefit.

But here's the rub. Assuming you've got a molecular hammer like Adcetris, and the molecular taxonomy of your disease - maybe it's cancer, maybe it's something else - implicates CD30 you know that you've got a high likelihood of some efficacy. Do you want to wait for a Phase III trial? No. Are you going to want to go into a placebo controlled trial? Or even a standard of care trial where you might get an untargeted treatment with serious side effects? No. And is your physician likely to prescribe the drug to you off label anyway? You betcha.

In these circumstances, the randomized clinical trial just doesn't make much sense. It's going to be overtaken rapidly by patients who know their own genomes, and the diagnostic tools that allow them to run N=1 trials that will allow them to rapidly screen drugs that might help them battle these diseases.

The key here is that you want a map of all the diseases that implicates this gene (or really, constellations of genes), and then you want to test the drug in these populations and find out what happens. Capturing that information and rapidly distributing it will be the coin of the genetic realm, leading to success for patients, regulators, and companies.

Safety, as Topol suggests, is something that we'll follow in the postmarket, because we'll have a confirmatory efficacy signal very early on with targeted therapies. Right now, the requirement for large trials that parse increasingly rare safety signals is the Berlin Wall facing drug developers, particularly for chronic diseases like obesity."

voraciousreader

AA....Thanks for posting these interesting developments in how genetic studies are in the process of changing how researchers are doing their research!  Hopefully, genetic research will get us much closer and faster to finding a treatment, a cure and a prevention of cancer and all kinds of other diseases.  Here's an article that appeared in yesterday's (May 13, 2013) New York Times with respect to researchers trying to find the genetics involved with causing heart disease.  I think it is obvious to all that the clinical trials that we have now are too expensive and too time consuming to help the folks that really need help NOW.  Without a doubt there is still a down side to genetic research not unlike the downside to current models of clinical research.  But the genetic research IS truly exciting.

"Seeking Clues to Heart Disease in DNA of an Unlucky Family

By  GINA KOLATA

    

Early heart disease ran in Rick Del Sontro’s family, and every time he went for a run, he was scared his heart would betray him. So he did all he could to improve his odds. He kept himself lean, stayed away from red meat, spurned cigarettes and exercised intensely, even completing an Ironman Triathlon.       

“I had bought the dream: if you just do the right things and eat the right things, you will be O.K.,” said Mr. Del Sontro, whose cholesterol and blood pressure are reassuringly low.       

But after his sister, just 47 years old, found out she had advanced heart disease, Mr. Del Sontro, then 43, and the president of Zippy Shell, a self-storage company, went to a cardiologist.       

An X-ray of his arteries revealed the truth. Like his grandfather, his mother, his four brothers and two sisters, he had heart disease. (One brother, Michael, has not received a diagnosis of the disease.)       

Now he and his extended family have joined an extraordinary federal research project that is using genetic sequencing to find factors that increase the risk of heart disease beyond the usual suspects — high cholesterol, high blood pressure, smoking and diabetes...

http://www.nytimes.com/2013/05/13/health/seeking-clues-to-a-heart-killer-in-the-dna-binding-a-family.html?pagewanted=all&_r=0&pagewanted=print

AlaskaAngel

VR,

The principles of comparison used for clinical trials now are resulting in very slow progress that is very expensive and far from adequate. Cheaper methods of genetic sequencing are bringing genetic study out for scrutiny as one alternative.

I can understand the attraction to all the techno-gadgetry, especially with younger generations spending most of their living moments plugged in or asleep. But given the soaring costs of supporting all of it, it would be hard to come up with the resources to pay for all that while at the same time paying for changing over to a massively different system for treating chronic illness based on genetic analysis.

Family illnesses could be genetic, or they could be environmental based on the family all experiencing the same environment and encountering the same unhealthy environmental influence(s. Either source could influence the other to become active when it might otherwise remain dormant.

Time will tell....

voraciousreader

AA....Genetic sequencing and technology IS becoming cheaper and faster....AND....technology is getting into the hands of the masses in many developing countries....Stay tuned!

AlaskaAngel

Here's another example, this time from urban Australia, regarding pancreatic disease:

http://www.theaustralian.com.au/news/matching-drugs-to-genetic-profile-of-pancreatic-tumours-could-unlock-cancer-cure/story-e6frg6n6-1226502671266

But once again, there is no information explaining the process for the initial creation and identification of the drugs that will be used for this effort to target genetic matches in treating pancreatic cancer.

Annicemd

AA so glad you started this thread, it will give us all food for thought

X

gpawelski

Good post AA. You have pretty much the right perspectives of what's going on. What happen just this week with Tarceva for lung cancer can be easily applied to any targeted drug in breast cancer.

The FDA okayed a diagnostic test for Tarceva. This area of pharmacogenomics (marriage of pharmacology and genetic testing) was ripe for proprietary tests, invented alongside the drug and owned by the drug developer and/or a partner in the diagnostics field. This business opportunity evolved as more drugs were approved with companion diagnostics.

Unfortunately, the introduction of these new diagnostics has not been accompanied by rational and economical use of the drugs. The headlong rush to develop companion diagnostics to identify molecular predisposing mechanisms does not guarantee that a cancer drug will be effective for an "individual" patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different targeted cancer agents of the same class.

They tend to only answer a targeted drug-specific question and may not address other important clinical decision needs. These companion diagnostics are being pushed to predict responsiveness and determine candidacy for a particular therapy often included in drug labels as either required or recommended testing prior to therapy initiation.

Landscape trends suggest companion diagnostic tests in their current "one- test/one-drug" embodiment will not adequately cover decision support needs as physicians become inundated with more biomarker data likely to be interrelated, nuanced and at time even contradictory. I would not want to be denied treatment with EGFR antibody therapy because of gene testing. Gene testing for EGFR is not a clear predictor of a lack of benefit from particular targeted therapies.

You can have tumor analysis (genotyping) coupled with clinical trial literature search, which tries to match therapies to patient-specific biomarker information to generate a treatment approach. In other words, information that may help when considering "potential" treatment options (theoretical analysis).

Or you can "actually" measure (phenotyping) the response of the tumor cells to drug exposure. Following this exposure, measure both cell metabolism and cell morphology. The integrated effect of the drugs on the whole cell, resulting in a cellular response to the drug, measuring the interaction of the entire genome.

AlaskaAngel

Hi!

It is nice to see there is some interest in taking a good look to check and discuss the foundations of the concepts that are being proposed.

If the focus of future development of medical practice includes greater use of sophisticated technology, okay. However.... the convenience or exploration of new technology seems to be a great "selling point" to get people to buy into the idea without really focusing on the end product. I'm not big on tech toys. To me the end product is far more important than new technology for convenience's sake. And to me the end product involves finding the greatest potential for the most successful treatments, whether they are "natural" or synthetic.

Topol indicates that he is relying on "popular support by the people" for initiating his recommendations. In response, being clear about the importance of putting in place the best possible unbiased process for the selection of substances for testing could make a difference in what we end up with.

I wish the people who conduct the interviews about matching drugs to genetic profiling would work a little to pin down these essential details.

A.A.

AlaskaAngel

Another question I have about "finding the treatment that matches each genetic mutation" is the question of just how do we identify whether any given mutation actually leads to a cancer that should be treated in any given patient?

Does each patient's immune system, for example, make a difference in whether or not that genetic mutation is actually a threat to particular patients? Do we need to also identify each patient's own "matching ability to treat" a specific genetic defect that patient happens to have?

jenrio

Good thread Angel.

Since Herceptin started the trend, there has been several very good drug developed for various mutations for various cancer:

Tarceva, Xykori, Yervoy

The more information we gather, the better we would understand, the better we understand the more likely treatment would be invented to cure.   

Our understanding of our body is like our understanding of the earth.   For thousands of years, we only have very coarse census information about a city.   The census information becomes finer grained.  Then genome information is like a terrain map of a city, RNA expression information is like sattelite map of a city, proteinomics information is like heat map of a city.

The cause and effect of how the body works are like the cause and effect in this city.   Different maps provide different insight.  The genomics information are the beginning.   A vast investment needs to be made into making sense of the information and do something about it.

voraciousreader

http://www.nytimes.com/2013/07/14/opinion/sunday/do-clinical-trials-work.html?hp

Following the annual ASCO meeting, Clifford Leaf wrote this op-ed piece in The New York Times asking, Do Clinical Trials Work?

He envisions future clinical trials to be genetic based....EXACTLY like what Eric Topol, MD discusses in The Creative Destruction of Medicine.

gpawelski

Physiology Trumps Informatics

According to laboratory oncologists, much like genomics aims to unravel the structure of the genome, metabolomics focuses on understanding the many small molecule metabolites that result from a cell's metabolic processes.

There are an estimated 5,000 - 20,000 endogenous human metabolites, and analysing their production gives an accurate picture of the physiology of a cell at a given moment in time.

Whereas the cell’s genotype can predict its physiology to a limited extent, metabolomics also takes phenotype – and therefore environmental conditions – into account, allowing a more precise measure of actual cell physiology.

For research, the study of metabolomics provides the means to measure the effects of a variety of stimuli on individual cells, tissues, and bodily fluids.

By studying how their metabolic profiles change with the introduction of chemicals or the expression of known genes, for example, researchers can more effectively study the immediate impact of disease, nutrition, pharmaceutical treatment, and genetic modifications while using a systems biology approach.

Just as a cancer genome refers to the complete set of genes, the metabolome refers to the complete set of metabolites in a given tumor. You may need to have the metabolome as well as the genome.

There are many reasons why cancer cures remain out of reach, but several changes could be implemented immediately to increase the rate of success. One of them is the need to redouble the efforts in the study of basic metabolism and the growing field of metabolomics (the metabolome).

AlaskaAngel

VR,

I don't know if I am interpreting Mr. Pawelski's discussion and points correctly or not, but I hope I can explain some of what I saw in it, and why his comments and yours led me to post again here.

To begin with, I still don't see any discussion or a defined way for practical application of Topol's ideas in an ethical manner. I still am puzzling over just where the money would come from to provide a specific drug regimen, for example, for those who happen to be a minority with cancer characteristics that only would be present for so few, since individual drug development is so expensive. I also don't yet see the "how" behind his proposed system in regard to the process of developing each drug for each person.

I think Mr. Pawelski's comments relate to my post in another forum here, about the importance of understanding not only the genetics but the exposures one has, in determining what treatment to apply. I hope Mr. Pawelski will correct me if I'm off track here. Here is my post from the other forum to consider:

http://community.breastcancer.org/forum/80/topic/764183?page=621#post_3631467

Thank you both.

A.A.

gpawelski

I've written about the epigenetic factors of cancer for the last several years on cancerfocus. As it becomes more of an accepted science, perhaps researchers will look at the next step and ask what role epigenetics plays in reversing cancer and what lifestyle decisions and exposures may impact such a role.

Perhaps some resources that are focused on the mechanistic, reductionist and overwhelmingly failed gene therapies can finally be redirected. I thought that would happen with NCI's efforts to award needed funds for this endeavor. In 2009, Johns Hopkins and USC were awarded $104 million to study cancer epigenome.

Evidence from some of their research suggests that the epigenome can be influenced by the environment which means that epigenetic modifications that lead to carcinogenesis may be reversible by changing the environment. And what is meant by environment is the totality of surrounding conditions - the milieu of the cell. What affects the milieu of the cell? Toxins, viruses, carcinogens, diet, essentially everything that our cells are exposed to.

Such a concept is heresy to the orthodoxy within the oncology community that determines research priorities. The viability of removing toxins, viruses, carcinogens and other biological contaminants from the body, followed by improving what a patient consumes (organic, whole, vegetarian foods, vitamin supplements, etc.) as a cancer therapy has been summarily rejected by the cancer establishment for decades.

AlaskaAngel

Thanks, Mr. Pawelski, for continuing not to let that important perspective get lost in the shuffle of excitement about genetic analysis as being "the" method for targeting drug development.

A.A.

violet_1

Love this thread/great minds here...will go back and digest the info/articles soon...

A.A., Thanks for starting this... YOU ROCK!



P.S.

I met Alaska Angel in person recently in Sacramento...She is a gem! Smart Cookie..;)

We had some fabulous discussions!



violet...Ann Marie