Simulacrisation in Drug Development. Part II.

Many Cancer Studies Are Actually Unreliable? Are you surprised? Definitively not: it is very logical and expectable due to the majority of trials are conducted by Big Pharma and their intellectual efforts in the field of research and science is very limited. We have already proven that the research which is conducted by Big Pharma or academia (sponsored or patronized by Big Pharma) simulates the real investigations of the Nature.

“Over the past decade, before pursuing a particular line of research, scientists (including C.G.B.) in the haematology and oncology department at the biotechnology firm Amgen in Thousand Oaks, California, tried to confirm published findings related to that work. Fifty-three papers were deemed ‘landmark’ studies (see ‘Reproducibility of research findings’). It was acknowledged from the outset that some of the data might not hold up, because papers were deliberately selected that described something completely new, such as fresh approaches to targeting cancers or alternative clinical uses for existing therapeutics. Nevertheless, scientific findings were confirmed in only 6 (11%) cases. Even knowing the limitations of preclinical research, this was a shocking result.”

Only 11%! It is not funny anymore! Sure, it is shocking for those who do not understand the new rules of Big Pharma game. Academia and Big Pharma are involved in production of simulacra and it is not surprised that their “research” is not reproducible (i.e. ontologically consistent). And it was already discussed earlier:

Unfortunately, Amgen’s findings are consistent with those of others in industry. A team at Bayer HealthCare in Germany last year reported4 that only about 25% of published preclinical studies could be validated to the point at which projects could continue.

The author is trying to describe the process of the simulacra production:

What reasons underlie the publication of erroneous, selective or irreproducible data? The academic system and peer-review process tolerates and perhaps even inadvertently encourages such conduct5. To obtain funding, a job, promotion or tenure, researchers need a strong publication record, often including a first-authored high-impact publication. Journal editors, reviewers and grant-review committees often look for a scientific finding that is simple, clear and complete — a ‘perfect’ story. It is therefore tempting for investigators to submit selected data sets for publication, or even to massage data to fit the underlying hypothesis.

The key words here are: “perfect story” and “data massage” – they are very important to the production of the miracle cure against cancer: the compound X inhibits receptor Y and in this way interacts the pathway Z etc etc.

Well, but what does the author propose? Guess what? More research, more work, more time and more money! Perfect – now there will be no choice even for simulated research to reach clinical trials! It will be even harder to cross the Valley of Death! But not for partisans of Valley of Death who know the situation and will use their knowledge to make huge profits.

Big Pharma Lobbying in EU

In one of my previous post I have assumed that Big Pharma constantly lobbies different types of authorities and here we have very nice example concerning EU: Big pharma spends 40 million euros per year lobbying in EU. Not bad!

“The pharmaceutical industry lobby is spending more than 40 million euros annually to influence decision-making in the European Union, of which nearly half is spent on in-house lobbyists.

“With the "immense disparity between the affluence of public interest groups and the industrial lobby, it becomes even more difficult to level the policy playing field", the report notes. Furthermore, it adds that many pharmaceutical companies lobbying the European Commission on legislation fail to declare their activities.

 HAI Europe and CEO note that as registration to the transparency register is voluntary, many pharmaceutical companies choose not to declare their spend. If recorded properly, they claim that "expenditure on lobbying activities by the industry could be shown to be as high as 91 million euros annually, which would be more comparable with the lobby spending declared in the USA; the report estimates that 220 lobbyists are active in the EU on behalf of the sector.

 HAI Europe project officer Katrina Perehudoff said the pharmaceuticals industry "has a significant presence in Brussels, and is clearly spending considerable sums of money on lobbying. This information should be available so that decision makers have a clear idea of the level of industry activity – but at the moment we only have a partial picture.”

Well, you see that authorities are motivated to play on the side of Big Pharma. And they play on the side against Partisans of Death Valley.

Life is life! Music of the week

Good buy, Whitney!

Mind-bursting!

By reading Pereslegin’s last book (see also here) I encounter unusual but perfect terms and sentences such as:

Creative generator, semantic transformer, intellectual row material, technological packet, trialectic form of technological balance, communicational, metaphoric and quantum protocol, technological space, engineric ontology,  engineric enginery (metaenginery), chaos engineering, forecasting engineering, non-progressive mankind,  ontological safety, high-tech destruction of the economy, mental or imaginary space, post-modern as a combinatorics of wasted ideas, planetary reflexion,   one-point extrapolation (perfect!), ontological hunger, cultural pillage (well…),

Mind-bursting phrases, many thanks, dear author…

Nanoscience: 3rd generation of nanoparticles is coming…

Well… It is no joke! The 3^rd generation of LNP (lipid nanoparticle) is on the way to be launched! The only problem is that nobody clearly understands this technology (see also here and here), even its 1^st or 2^nd generations. Let’s see for the explanation:

LNP technology for indications involved with the liver is the most mature delivery system within RNAi therapeutics. Current LNP (lipid nanoparticle) technology is in its 2nd generation (such as ALN-PCS, ALN-TTR02) which has ~100-fold increased potency and better safety than 1st generation (such as ALN-VSP, ALN-TTR1) offerings.

One of the issues with the current 2nd generation LNP is that they have long elimination half-lives in plasma and tissues. It is suspected that they might accumulate over time and lead to cytotoxicity in target cells with chronic dosing. Specifically, they end up building up in the liver and spleen.

The idea behind the new 3rd generation LNP technology being researched by Alnylam (ALNY) is to create a rapidly eliminating LNP formulation (reLNP). The idea behind reLNP is to have them be rapidly biodegradable so this accumulation cannot occur. Observe these preclinical results of how these rapidly eliminating LNP are eliminated in the plasma, liver and spleen. It looks like 2 reLNP lipids are being evaluated with different elimination half-lives. I assume that 2 reLNPs are being researched so further experimentation can find the sweet spot for therapeutic application.

Then we can see a lot of experimental pics in the rest of the article clearly convincing us in the advantages of the 3^rd generation of LNP. Basically I think it is worth to continue developing the new generations of LNP if the former ones were not efficient in the creation of new efficient drugs. I hope that 30^th or 50^th generation will be definitively successful – just not to give up!

Where money is going...

There are different ways of calculation how much does cost a development of a new pharmaceutical product but it is obvious that the efficiency of drug development is gradually decreased and it takes more and more resources for launching of novel drugs.

Let's analyze where these resources are being pumped. Let's take a look on the typical development process:

Here we have huge holes where money is disappearing:

1.    Cellular and genetic targets – in order to start the development the targets have to be specified. Well, I can argue that there are a lot of efficient drugs out there with unknown mechanism of action, so this step can be successfully omitted.

2.    Genomics – very huge hole. The idea “gene – protein – drug” or “key-and-lock” is extremely simplified, mechanistic and not scientific anymore.

3.    Proteomics – the same situation as for genomics.

4.    Bioinformatics – I think that this discipline was invented exclusively in order to find out any possible application of enormous bunch of the data from genomics, proteomics etc.

5.    Now we came to synthesis and isolation – very classical step in drug development process. But wait a minute – it is not the same synthesis anymore, it is not enough to synthesize and isolate a putative drug candidate – it is too simple! In modern epoch everything has to be automated and scaled up, therefore huge libraries of hundreds or thousands of compounds are produced by approach known as “combinatorial chemistry”.

6.    Combinatorial chemistry – a perfect tool to consume huge amount of money and time. And it gives rise of huge amount of crude compounds which are tested then on different types of assays.

7.    Assay development – well, it sounds scientific – and this process, guess what? - need also certain amount of resources!

8.    HTS – this is the crown of the whole concept – it is very often fully automated process which is always presented in action to the attention of investors during their visits to the drug development companies (I have this experience! This technique is really amazing)

9.    Library development we have already discussed in §6.

10.  Structure-activity-studies (also known as SAR) – this is completely alchemical or star-counting process which is beyond any rational understanding. Here basically can be spent any possible amount of resources: $1M or $100M – only fantasy matters!

11.  In silico screening – well, there are a lot of mathematicians out there, they need job and this field is specially invented to provide these job positions for mathematicians. Nobody cares and even understands the results of their calculations. There is no any rational how their numbers can be used in drug development.

12.  And finally, we came to the classical chemical synthesis.

13.  Drug affinity and selectivity – but who said that drug has to work selectively on special target??? If it doesn’t work selectively on a special target but have a hundred of different targets, does this drug have any chance to be an efficient medicine? The current paradigm has to say “NO”!

14.  Cellular disease model – it is relevant only for the minority of diseases.

15.  Mechanism of action – so the drug is efficient if we understand the mechanism of its action? - It is bogus.

16.  It is very broad statement, let’s skip it.

17.  And finally we came to in vivo. Here according to my understanding starts the real and productive science!

 

Well, you see and understand now why the process of drug development is so expensive! It is necessary to pay all the way for points 1-11 to fit your product in the modern paradigm. Then it is possible to brag that the drug has special mechanism of action, it selectively targets a receptor X and deactivates mechanism Y etc etc. But it has nothing to do with the Evidence Based Medicine – the ontology of the drug action which probably our last safeguard.

Help to Partisans of Death Valley!

EU govts urged to ensure R&D is converted into new businesses and jobs. Yes, the intention is good.

“Governments in Europe need to do much more to ensure R&D innovation in biotech industry is translated into new businesses, new products and additional jobs”

And the proposal is outstanding! Just look at this:

“The report surveyed 16 countries across Europe and compares the tax concessions on offer in each country, financing opportunities for small and medium-size enterprises, "and the benefits that can flow from a decision to establish a start-up in a particular location". It notes that the continent "has the potential to be a world leader in the field of biotechnology" but "it is not enough to have a good tax or finance system in place. The right policies and incentives for R&D development are also essential to growth in this industry".

This is exactly what we need to cross the Death Valley – only start-ups, the partisans in this area of drug development, can do that. I hope that the help will come!

Partisans of Death Valley

I have written a lot of critical words regarding Big Pharma model to simulate conduct development of new drugs. And I have also written a couple of words that the current environment is extremely profitable for those who has novel ideas and dire to challenge Big Pharma, those who can fight in Death Valley to transform these ideas in new concepts, products, treatments, approaches resulting hopefully to change the current paradigm. These fighters can be called as Death Valley partisans because they are struggling for development and commercialization of novel science behind the front line of Big Pharma, they suffer very much from the traps and mine fields arranged by authorities and Big Pharma in a form of hard rules and guidelines, they are waiting silently in low-budget ambush until they find the best situation to make a shot not having any chance for the second attempt. They have it pretty hard but they are waiting for the jack-pot. For awfully big rewards which has to compensate all their straggle. On the other hand I don’t think that the main motivator is money. Their creativity, their principles, the desire to make it happens, to internal demand to build something novel, useful and original are the main driving force for these men and women. They work hard and deserve to be prized.

And here is the nice description of how a business model of Partisans of Death Valley can look like:

"In the meantime, one biotech model gaining traction is the single asset, infrastructure-lite, development model, which deploys modest amounts of capital to develop a single compound to an early clinical data package which can be partnered with pharma. The asset resides within an LLC, and following the license transaction, the LLC is wound down and distributes the upfront, milestone and royalty payments to the LLC members on a pro rata basis. The key to success in this model is choosing the appropriate asset/indication – one where it is possible to get to a clinical data package on limited capital. This approach excludes many molecules and indications often favored by biotech, and tends to drive towards clinical studies using …"

So true! And I agree with the author:

"Amidst all this turmoil a couple of things remain constant. The pace of innovative research and discoveries by our talented scientists in the public sector has not slowed; and pharma’s need for promising compounds is more dire than ever. However, the way in which one reaches the other is in flux at the present time, presenting a challenge but also an opportunity. In its latest efforts, pharma seems to be trying to sidestep the richly priced acquisitions and licensing deals of previous years by cutting out the middle market and going directly to the source – with a recent trend for generously funded research collaborations being doled out to top tier universities. Whether pharma has the agility to stock its pipeline through this mechanism without relying on biotech companies seems unlikely."

Good luck, Partisans, I am playing on your side!

Drug Development Process: Pictures in Color…

The drug development paradigm (the current way of thinking accepted by the majority of the player in this field) can be graphically presented in different ways. Sometimes the simplified sketch is very useful to have a helicopter view over the drug development landscape. I have briefly searched through google and find a couple very nicely designed pictures:

As you can see the paradigm has been depicted in different ways, by different arrays and models, in a similar way compared with trends in the art:

No entry even for Dirty Swans

So far I am convinced that stem cells’ approach in medicine is a Dirty Swan. A lot of resources were spent in a veil without generating any promising drugs and treatment. The rhetoric of stem cell approach followers is extremely optimistic, just look at this:

 

And what is absolutely expected, this method was criticized by FDA, so if this approach would be worth anything – it would be stopped by the authorities! The market is absolutely secured from even Dirty Swans!

Let's try again...

Targacept reports mixed data from two trials (see also here):

March 27 (Reuters) - Targacept said an experimental drug proved effective in a mid-stage asthma trial, but failed to meet the main goal in another trial for type 2 diabetes.

Well, a nice idea to conduct different clinical trials simultaneously! Think that the similar approach was used to find the magic action of Viagra!  Why didn’t test the drug against tens different types of cancer, AD, Parkinson’s, etc? It could hit somewhere!

Another cure from cancer

Several times per year I encounter articles in different popular magazines or news sites bragging that scientist X from the university Y has found a way how to cure cancer (or AD or whatever). This time we have the following article. Well, you can assume that it can be true, and the scientist X probably is right and the disease will be cured very soon, however, using usual method of induction we can prove that the chances are extremely low... But the publicity is there and scientist X from university Y is a hero of the day!

Antibodies are coming...

New Cholesterol-Lowering Drugs Will Test the Future Healthcare System! (Another link is here). And now the drug in question is extremely expensive antibody! Why not?  Small molecules are cheap and not sexy any more.

“We are now in a world where generic statins exist.  Over the coming months, the cost of therapy for even high doses of atorvastatin (the active ingredient of Lipitor) might be as low as $1 per day.  Antibodies, on the other hand, are expensive with the majority costing tens of thousands of dollars per year.  Insurance companies and other payers will undoubtedly look at this situation not necessarily with regard to the degree of LDL lowering provided by these compounds but rather with regard to cost.  Why reimburse the costs for a PCSK-9 antibody at $20,000 per year when a generic statin at $400 per year is almost as effective? “

Antibodies (proteins) have a lot of advantages from Big Pharma point of view:

1.       Antibodies are complicated structures and it gives an impression of high intellectual content of the medicine.

2.       Antibodies are complicated and the higher price is motivated

And who cares that the new drug is injectable and less practical compared to usual statins?

Another day, another Dirty Swan…

Black Swan will come in the similar way...

An impressive storm

Simulacrization of Music Industry?

”Opened world of creativity...” leading to... ”global masturbation?” They are calling this for ”Democratization … by … mediocrity”... Well, you can see how simulacra are produced.

Black Swan in energetics???

Dirty Swans – pros and cons

It is understood that recognition of any coming wild cards (Black Swans) is similar to prediction of the future and can be extremely profited by a person or organization that are able to make such recognition. Investors of any kind place their bets (time and money) on different innovations in a desperate hope that the innovations will revolutionize our lives, economy or science. If the changes made by the innovations are not in a scale to dramatically change our world, well, these innovations can be considered as Grey Swans.

Then we have innovations which were expected to be very important however their benefits and advantages (if any) became very modest. We have coined the name for these innovations: Dirty Swans. As a very good example of a Dirty Swan is a nanotechnology (inclusive nanomedicine, nanobiotechnology, bionanotechnology and similar nanoscience). There is a hope among investors, politicians and scientists that nanotechnology will provide unique solutions for existing problems and will radically change the World we are living in. I would be also very enthusiastic in this issue, however it is very remarkable that nanotechnology is not consistent ontologically – there is no any real scientific (even sci-fi’s) background for these positive expectations.

It is obvious that Dirty Swans slow down the progress by attracting valuable resources as time, money and PR from another, more ontologically consistent and promising fields of research. And the main beneficiaries of the Dirty Swans are:

1.       Big Pharma – Dirty Swans prevent  immaterial assets of Big Pharma from devaluation caused by new research, discoveries and products

2.       Worlds Economy – may be paradoxically, but a Dirty Swan (as well as Grey and really Black Swan) gives the possibility to pump in the Swan’s development a lot of money and the money being consumed stimulates the extensive evolution of the economy.

3.       Political elite – it is profited through political control over the situation.

Who stays on the opposite side? Who are beneficiaries of a Black Swan?

1.                        Big Pharma’s “conter-elite”. In the pharmaceutical industry always exist some companies who would like to challenge those who are sitting on the top, and any Black Swan is a perfect weapon in a war between pharmaceutical competitors.

2.                        Political counter-elite – it can take leading positions only through radical changes in the society and economy.

What is the final verdict? There is nothing wrong with the existence of Black or Dirties Swans, - the critical question is: “Which side you are playing for?”

Black, Grew and Dirty Swans: Application of Metaphoric Ornithology

The current paradigm of drug development and pharmacology will be changed sooner or later and those who will recognize the change will be able to take a major profit associated with the paradigm shift. A phenomenon which induces this kind of shift is usually called as a wild card or Black Swan in Nassim Taleb's terminology. In the history we can recognize several wild cards which dramatically changed the medicine and in this way made a significant impact on the civilization. Examples? Well, vaccination which eradicated a lot of dangerous infections and prevented pandemias. Another more recent example is discovery of penicillin and other antibiotics. In oncology we can mentioned discovery of curative effect of mustard gas on leukemia patients.

Well, let's take a closer look on the situation with natural science. The last Black Swans were: quantum theory, discovery of hormones and vitamins, nuclear fusion and synthesis, genetics, cybernetics with IT, internet, NLP and cognitive science. Well, probably I missed something. Then we have a lot of important phenomena, very crucial events and discoveries which could make a huge impact on the mankind but by some reasons the impact was not very huge. Let's call these events as Grey Swans. Examples? Personally I would name transplantology – it is proven to be possible and even now very usual to conduct organ transplantation but it doesn't changed very much the society. Another example is a space flight inclusive Moon expedition – very interesting event which didn't changed people very much. Genomics, stem cell discovery, renewable energetics... You can also find another good examples. The Grey Swans can probably lead in the future to bigger changes becoming in this way really Black Swans. May be in a very long perspective.

But there are a lot of disciplines and events which pretend to be very promising and important in the same scale as a Black Swan but in reality which are not inducing any remarkable impact on the global level. Let's coin a name for them: Dirty Swans. Intuitively the name is understood: Dirty Swans are look like Black ones but being simply dirty they can be “cleaned” into “usual” and not very important White Swans by close critical scientific analysis of their potential and practical merits. I would suggest the following nomineeo be named as a Dirty Swan: nanotechnology (inclusive nanomedicin, nanochemistry etc), biotechnology, ecological science inclusive global warming, combinatorial chemistry and HTS. The list of Dirty Swans will be constantly updated – in the search of a really Black Swan we will clean every Swan available for our critical analysis.

Nikola Tesla's Experiment?

Where is the trick? Is it possible? The patent is not enough... Where is a pilot station?

And a funny experiment with Tesla's Transformator:

Demodernization, Ecological Movement Etc

A.I. Fursov. Any comments?

The Science Was Transformed to Cryptomathics

Probably the most famous video of A.I. Fursov. Impressive!

Cognitive Treatment and Semantic Pill: Future of Medicine (forecast)

Everybody knows what “placebo” means:

(Wikipedia) A placebo ( /pləˈsiboʊ/; Latin: I shall please) is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient. Sometimes patients given a placebo treatment will have a perceived or actual improvement in a medical condition, a phenomenon commonly called the placebo effect.

It is not so widely known about a nocebo:

(Wikipedia) In medicine, a nocebo reaction or response refers to harmful, unpleasant, or undesirable effects a subject manifests after receiving an inert dummy drug or placebo. Nocebo responses are not chemically generated and are due only to the subject's pessimistic belief and expectation that the inert drug will produce negative consequences.

In these cases, there is no "real" drug involved, but the actual negative consequences of the administration of the inert drug, which may be physiological, behavioural, emotional, and/or cognitive, are nonetheless real.

Another interesting word “cognitive”. Well, another definition:

(Wikipedia) Cognitive science is the interdisciplinary scientific study of the mind and its processes. It examines what cognition is, what it does and how it works. It includes research on intelligence and behavior, especially focusing on how information is represented, processed, and transformed (in faculties such as perception, language, memory, reasoning, and emotion) within nervous systems (human or other animal) and machines (e.g. computers). Cognitive science consists of multiple research disciplines, including psychology, artificial intelligence, philosophy, neuroscience, linguistics, anthropology, sociology, and education.

Well, without going into details and not mentioning NLP and other relevant research I will just mention that it is widely accepted that our mental activity undoubtedly affects our bodies and physiological health. But why this phenomenon is not used? Or, to be correct, not widely used? In any way it is not a competitor for Big Pharma drugs in its scale. In usual pharmacological treatment a patient takes a drug, the treatment can be scaled up and protocolized in such a way that almost everybody can understand how the drug can be used and a patient treated (as soon as a disease was diagnosed and the drug is prescribed). This scheme is successfully commercialized and profited by Big Pharma. In the case of cognitive treatment of let's say a cancer, a patient supposed to be in close contact with a doctor or a specialist in this field of treatment. The main curative effect is provided by not a pill but a service of a specialist in cognitive medicine. Big Pharma in that case is not able to sell anything in a large scale to the cognitively treated patient – the main profits are maid by the specialists providing the cognitive treatment to the patients...

We have some kind of conflict here: Big Pharma (and nobody else) possesses necessary resources for the development of the cognitive treatment but is not able to commercialize it a usual pill-selling way. There are no any other players on this area who could develop the novel cognitive approach. How to solve the contradiction?

Let's make a forecast:

Scenario A:

Big Pharma patents the protocols of cognitive treatment and then licenses out these protocols to hospitals.

Scenario B:

Big Pharma develops novel types of drugs – let me coin a name - “semantic pill”, some kind of mantra, talisman or icon which could provide a desired curative effect by using them in a proper way.

Scenario B sounds very … non-scientific. I do agree, but the placebo and nocebo phenomena are there, they are real and I think and hope that it is a question of time when this scenario will be a standard medicinal procedure. I guess that the futuristic scenario B will be available somewhere 2100-2200. Scenario A is less revolutionary and can be available already 2050 – exactly when we will need it!

Music of the week

The Race - Yello

Music of the week

Diva Plavalaguna featured by the Perfect Being

Simulacrisation of Drug Development

From Wikipedia:

Simulacra and Simulation is most known for its discussion of symbols, signs, and how they relate to contemporaneity. Baudrillard claims that our current society has replaced all reality and meaning with symbols and signs, and that human experience is of a simulation of reality. Moreover, these simulacra are not merely mediations of reality, nor even deceptive mediations of reality; they are not based in a reality nor do they hide a reality, they simply hide that anything like reality that is irrelevant to our current understanding of our lives.

Did you catch the message? Once again: our current society has replaced all reality and meaning with symbols and signs, and that human experience is of a simulation of reality.

It is no need to be a philosophe and read anything more from Baudrillard to see how his definition of simulacra perfectly suits to modern drug development process. We see that a lot of resources are invested, huge amounts of data and scientific literature are being published, tons of patents are issued – but the productivity is dramatic decreases.  And all this nanotechnology, biotechnology, genomics, nanobiotechnology, bionanotechnology, personalized medicine etc – it is not the real development, it is the simulation of the development - they are just simply perfect designed simulacra to take our attention from the real problems based on real material, sensual and otherwise ontologically based issues.

Well, what can be on the opposite side of simulacra? Ontological drug development as a novel old field of research and creativity.