Patient Genetics and Online Collaboration

Is the future in controlled clinical trials, or IT driven collaborations to share health experiences? The answer is obviously a mixture of both, but patient/industry collaborations are making some very positive steps towards becoming a powerful tool.

This great article from NYTimes highlights some collaborations already formed.

For example, in June this year, the Belgian pharmaceutical company UCB announced a partnership to build an online epilepsy community with PatientsLikeMe, among the first private companies to develop a platform for data sharing by patients. PatientsLikeMe, based in Cambridge, has as members tens of thousands of patients who contribute detailed information about their diseases, drugs, doses and side effects. Mark McDade, UCB’s chief operating officer, said the regulatory approval process should be changed to incorporate not just safety and efficacy but also measurements on how drugs affect patients’ lives — data that is now slow and expensive to collect.

Genetic companies have also taken up patient-driven research. The Silicon Valley company 23andMe, for example, started a program this summer called “Research Revolution.” People can buy a stripped-down version of 23andMe’s genetic service, which gives people DNA information on ancestry and risk for certain diseases, for $99 and then contribute their genetic data toward research into the disease of their choice (NYTimes).

Are Placebo’s Getting More Effective?

At least some people believe they are – particularly those drug companies whose pipeline champions are being sunk by the famous effect. This Wired article offers a great list of drugs recently entombed by the placebo effect. It also explains it’s history and the concern it is causing in drug development. But I disagree that the placebo effect is ‘increasing’ as they suggest.

The drop in drug approvals they cite and many of the specific examples they give are probably not due to an ‘increasing placebo effect’ but poor trial design, less effective new therapies and the lack of low hanging fruit. I would even suggest that the perceived change in the effectiveness of Prozac is actually the result of better experimental measurement leading to better data that demonstrates what clinicians have always known.

Trials are becoming harder to design as there is less money available – in part because potential profits from new drugs are not what they used to be. Studies are ‘powered’ at an absolute minimum, and resources sent offshore to clinics with high capacity but lower quality guarantees. This is of particular concern in studies where drug efficacy is highly dependant on patient or clinician reporting rather than hard measures such as well defined lab tests. They Merck scientist in fact demonstrates this when he says they saw different effects in Spain and France.

They author also fails to mention that many new drugs being trialled are in therapeutic areas fairly well served by existing drugs. there is less room for improvement and therefore it is harder to create more efficacious drugs. Early phase testing is easily misleading due to small sample size and other biases.

When the article delves into the cognitive neuroscience behind the placebo effect they indeed point to the fact that by definition, the placebo effect can’t ‘increase’ unless the human brain changed substantially in the last 40 years.

Despite this it is a great article and I look forward to hearing more about the Placebo Response Drug Trials Survey.

Genome and Metabolic Scans the new anti-Cancer Weapon

New cancer treatments are one of the most precipitous of all drugs to develop. But a renewed focus on the DNA mutations that make each cancer unique is about to expand our ability to find new treatments.

Cancer biomarkers may be detected using Mass Spectrmoetry

Traditionally, cancer drugs have been developed by identifying compounds, more recently antibodies, that have a highly toxic effect on cancer cells and animal models in the lab. They are then tested on small, then larger groups of patients to prove their efficacy. But this model is yielding less and less success. In the last 30 years, for example, there has been no real improvement in the drugs able to treat metastatic melanoma from which about 1000 Australians die every year.

The reason is that scientists have been slow to figure out ways to truly capitalize on our molecular knowledge of cancers. Our approach to disease is very linear – X mutation leads to Y disease – despite us knowing that most diseases are polygenetic in origin.We tend to work on particular molecular pathways in isolation. For example, individuals labs will often use one animal model for their own research.

In this article, the founders of Sage, a biomedical networking company, explain how our approach has to begin to use our knowledge of full molecular networks. They say that much of Merck’s metabolism pipeline was developed using such molecular knowledge.Another great example is the AstraZeneca/Biowisdom Safety Intelligence Program (SIP), described as the “largest forever-expanding collection of known chemical effects occurring in different tissues, drug effects on clinical biomarkers of tissue injury, and drug molecular mechanisms.” Currently, SIP contains almost 100,000 individual facts, or “assertions,” related to the liver’s response to more than 5,500 different compounds in over 20 species.

Fundamentally, this new style of research relies on powerful new approaches to sequencing and decoding genomes – something that DNA arrays initially promised, but never really delivered. I’ve previously written on this topic, but every month new astounding results come out of cutting edge labs that herald a new era in molecular science and particularly cancer treatment.

Helicos Biosciences, a company founded in 2004 to commercialize single DNA sequencing technology has just become the fourth next-gen sequencing platform to complete a genome. At the same time, a second leukemia genome has been fully sequenced leading to discoveries of previously unknown mutations and new potential drug targets.

The next step is to capitalize on these discoveries by testing the association between these markers and the various drugs on offer. As an example, these researchers at MIT have found that when both p53 and ATM (common tumor markers) are abnormal, tumors are highly susceptible to DNA-damaging chemotherapy. Tumors in which ATM is mutated but p53 is not, are highly resistant to chemotherapy. Tumors in which p53 is mutated but ATM is not seem to be less responsive to chemotherapy.

This is a solution that is applicable immediately. “You could use this today,” the author says. “You do immunohistochemistry for the tumor, for p53 and ATM, and based on [the results] you can choose anthrocyclines [if appropriate], or taxol as an alternative based on this data.”

Drug companies are beginning to use bio-markers more and more in their studies, but I would contend still not enough. If you do a medical literature search of recent cancer clinical trials, how many trials report collecting bio-markers such as p53 and ATM?

In a closely related field – metabolic profiling–an analysis of chemical reactions in the body- there has been a positive recent advancement. Metabolic profiling may help optimize drug use in patients.

Today, most doctors rely on broad measures like weight, sex and age to determine which drug and dose is most likely to be effective. It’s a notoriously hit-or-miss approach that commonly requires follow-up doctor visits and changes in drugs and dosing. Now are groups of UK scientists have determined that the chemicals created during the process of metabolism and then excreted in the urine could be a more effective tool for personalizing therapies.

To test their theory, scientists at Imperial College London and Pfizer took a urine test of 99 men who were given paracetamol, a common painkiller. What they found was that ascertaining the level of a compound in the urine–para-cresol sulphate–gave the scientists a clear picture of how the men would metabolize the drug. Higher levels of the compound, which is produced in the gut, indicated that men would metabolize the drug less effectively. They theorized that higher levels of the compound indicated that their bodies were depleted of sulphur, which many drugs rely on to work safely. Sulphur helps to detoxify the body. Engineering the bacteria in the gut could fine tune how a body metabolizes a drug.

The advantage of this pre-dose metabolite profiling is that it related to both genetic and environmental factors influencing drug treatment outcomes. Again, this is another step that will soon put an end to centuries old hit-and-miss medicine.

US Politicians to Ban Drug Ads

Direct to Consumer, as it is known, is when pharmaceutical companies market their wares to the public. It is only allowed in a few countries like the USA and New Zealand, and with restrictions.

But a move is on to limit or ban them altogether. This NYTimes article explains the politicians motivations.

On the whole, I agree with the arguments presented there. To me it is another wake up call for the healthcare industry as it seeks new ways to interact with consumers and begins to realize it’s future lies more in wellness/prevention and personalised medicine than blockbuster products.

Clinical Trials Evolving

A NYTimes article, Lack of Study Volunteers Is Said To Hobble Fight Against Cancer, gives some stark statistics about the diminishing availability of patients for cancer trials, and hints at some of the broader problems in the world of clinical trials.

At a recent NHMRC Clinical Trials  meeting, several presentations dealt with the changing nature of clinical trials. The main challenges presented were:

1. Trials are being moved by companies to developing countries where trials costs are cheaper and more patients available.
2. Fewer trials are for drugs that will demonstrate significant improvements in efficacy. This in turn means larger numbers of patients are needed for the trial to demonstrate superiority.
3. New technology, particularly biomarkers, are both a benefit and a challenge as subpopulations of responders are identified and trials endpoints need to be shifted.

Overall, the feeling was that the current trial paradigm is far to rigid and expensive. The NYTimes article alludes to this strongly. One impressive stat they cite was that there are more than 6,500 cancer clinical trials seeking adult patients, according to clinicaltrials.gov. But more than one trial in five sponsored by the US National Cancer Institute failed to enroll a single subject, and only half reached the minimum needed for a meaningful result (reported in a recent review in The Oncologist). At California Cancer Care, in Greenbrae, north of San Francisco, they try to offer trials to every patient. Yet last year they enrolled just 43 of about 700 new patients.

While the US has it’s own health care issues that are partly impacting on trial uptake, these are ominous signs – to some.

My view is that these changes are part of the new world of drug development. We are moving towards streamlined naturalistic trials in a world replete with real-time patient outcomes data. The faster we run out of pointless trials for me-too drugs, the better.

Simple Inventions are the Best

And this is one example of haw a little creativity can go a long way!

Bob Terwilliger, a 64-year-old Palm Beach County native and multimillion-dollar businessman, came out of retirement to help Dr. Brian Kaplan’s create a rotating label on children’s medication that will base doses on a child’s weight and not age. It sounds simple enough, but the newly formed AccuDial Pharmaceutical Inc. is the sole medical company with the patent that could make it much easier for parents to determine how much medication their children should take.

Accudial Demo Bottle

Read the full story here.

It reminds me very much of a creative coach I know, Peter Harris, who was a print salesmen that made a small mint in his early career when he developed a rotating wheel of the weekends rugby fixtures around Sydney as a magazine insert.

Pharma backed Medical Education Under Fire

From FiercePharma:

Continuing medical education (CME) has been bastardized by pharma funding, an HHS inspector general told Congress, and needs a complete overhaul. Lewis Morris, chief counsel for the HHS office of inspector general, said that industry doesn’t just shape the courses, it has also used CME to promote off-label uses. And Morris was just the first of several witnesses expected to criticize industry-funded CME during a Senate Committee on Aging hearing.

Pharma-backed CME has grown by leaps and bounds. Dow Jones reports that industry funding for medical education has more than tripled over the past 10 years to $1.2 billion. That’s more than half the courses many doctors are required to take to stay current. “CME has become an insidious vehicle for the aggressive promotion of drugs and medical devices,” said Dr. Steve Nissen (photo), the Cleveland Clinic cardiologist who rarely minces his words.

But others–including PhRMA–protest that the industry can offer the best, most up-to-date info on new treatments, and that drugmakers are an important part of medical education. Dr. Thomas Stossel of Harvard Medical School–who has started an organization balking at the current backlash against pharma funding and doc payments–told the committee that companies make an important contribution to scientific understanding of disease. “I want the best information. I don’t care who pays for it,” Stossel said (as quoted by Dow Jones). “The nonprofit societies just can’t get up to speed fast enough.”

The hearing is just the latest salvo in an ongoing battle over how much pharma funding is too much, and whether all financial ties between industry and doctors, academia, and CME should be disclosed. Medical schools and hospitals have established conflicts-of-interest policies, some of which are so strict they don’t even allow reps to hand out logo notepads. Drugmakers have promised to disclose payments to doctors, and some have bowed out of CME funding. This particular Senate committee is considering legislation that would require companies to disclose doc payments. The debate is far from over.

Personalized Medicine at JnJ

It’s encouraging to hear that one of the worlds largest healthcare companies is investing heavily in personalized medicine. It is also interesting to note that they are aware just how expensive it is likely to be, at least in the short term, but never the less feel it is imperative to begin work now.

Read the article about Johnson and Johnson’s efforts here.

Pharma 2020: PwC Analysis

PwC’s latest industry synopsis offers some of the bleeding obvious, but also a few gems that I think companies are perhaps not too aware of.

The clincher for me is in the following excerpt:

Management guru Clay Christensen has convincingly demonstrated how disruptive innovations in various industries have dismantled the prevailing business model, by enabling new players to target the least profitable customer segments and gradually move upstream until they can satisfy the demands of every customer – at which point the old business model collapses.

Pharma is currently undergoing just such a period of disruptive innovation. By 2020, most medicines will be paid for on the basis of the results they deliver – and since many factors influence outcomes, this means that it will have to move into the health management space, both to preserve the value of its products and to avoid being sidelined by new players.

Indeed there is some partnering occurring. we are seeing pharma team up with devices groups and enlist all sorts of health-related technology companies.

The report mentions that several companies have already attempted to create disease management offerings, but met with no success. It highlights the shift towards outcomes measurement and personalized medicine.

My personal view is the following:

The ‘disruptive innovation’ will ultimately be consumer driven. Already consumers are trying to take control of their health related information and better measure the success of their treatments. In the same way that doctors will increasingly become partners in managing health (moving away from dictating treatments), industry will have to learn how to partner with patients.

Therefore the obvious next question is how industry, and particularly drug companies, can begin to partner with consumers? The answer, to me, is that the greatest asset pharma companies have is access to the drug-related information people need. Pharma’s greatest value in the chain of treatment is not in R+D, clinical trials, or health technology assessment – it is ultimately that as managers of the treatment-related information, it is in the best position to decide how a drug or other treatment can be used.

If they can link this knowledge to individuals health data then they can superceed other players.

To do this pharma needs to begin looking at information systems that will allow them to measure individual patient outcomes and provide adaptive feedback. It may require investment in the EHR space and other technologies such as mobile apps.

There are some barriers to dealing directly with consumers, more in countries like Australia than in the USA. This is then the first step – understand how this collaboration is going to work and what other players we need to engage to make it work.

For another synopsis of the PwC publication see FiercePharma.

Only Moore’s Law can save Big Pharma

An interesting article by Bill Frezza – read below:

If ever there was an industry at risk of being sunk by not one but three category five hurricanes, it’s the pharmaceutical industry. Whether it’s on the political, economic, or scientific front this major contributor to our nation’s financial and physical well being is headed for wrenching transformations.

Politically, Big Pharma is at the mercy of all three branches of an increasing hostile government. The executive branch, through its regulatory agencies, has raised the cost of product development to astronomical heights. The judicial branch, through its class action machinery, has made the penalty for delivering anything short of zero-defects untenable. And the legislative branch, on its way to becoming the industry’s monopsony purchasing agent, is hell bent to drive prices down to the marginal cost of production.

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Economically, Big Pharma continues to deliver less and less for more and more. A new blockbuster cancer drug is almost never a cure. The “good” ones have no effect on most patients besides making their hair fall out while helping some “fortunate” subset die in 15 months instead of 12. For some advanced biologics, this pathetic result comes with a sticker price of $100,000. The only reason there are any customers at all for products this bad is that someone else is paying the bills.

Scientifically, the classic drug discovery paradigm has reached the end of its long road. Penicillin, stumbled on by accident, was a bona fide magic bullet. The industry has since been organized to conduct programs of discovery, not design. The most that can be said for modern pharmaceutical research, with its hundreds of thousands of candidate molecules being shoveled through high-throughput screening, is that it is an organized accident. This approach is perhaps best characterized by the Chief Scientific Officer of a prominent biotech company who recently said, “Drug discovery is all about passion and faith. It has nothing to do with analytics.”

Does this sound like science to you?

The problem with faith-based drug discovery is that the low hanging fruit has already been plucked, driving would be discoverers further afield. Searching for the next miracle drug in some witch doctor’s jungle brew is not science. It’s desperation.

Read the rest of the article here.