Tuesday, December 30, 2008

Do Clinical Trials Take "Immoral Advantage of Patients"?

At least one patient thinks so. And he writes about it today in the Wall Street Journal's Opinion Journal under the title "The FDA Is Killing Crohn's Patients."

Do patients have a moral right to know their treatment group at the end of the study?
Do patients (in particular those from a placebo arm) have a moral right to access the experimental therapy when the study ends?
If such a moral obligation exists, does an informed consent absolve a sponsor?

In each of the stories that have come to the mainstream media over the past few months (including the case of Fred Baron seeking off-label Tysabri), there is seems the assumption that the experimental therapy is not only known to be safe but assumed to be effective.

As argued in the WSJ, the constitution should be interpreted to allow "a crtitically ill patient...access to a potentially lifesaving drug that has been deemed safe for human consumption, if the patient agrees to bear the risks involved."

But an IND to initiate human trials is based only on preclinical/animal testing -- a barometer few would interpret as a stamp of being deemed safe for human consumption. In fact, it's the very clinical trial being conducted that is meant to demonstrate safety during the drug's life as an experimental medicine.

And is a patient's signature on a consent going to be adequate to demonstrate that the "patient agrees to bear the risks involved"? In fact, didn't the patient sign a very similar consent agreeing to risks involved when signing on to the clinical trial (including those of placebo use)?

Patient rights are a moral obligation. But so too is patient safety, which much be the priority. Finding a common ground in the coming year will be important for ensuring patients feel both safe and not-abandoned in clinical trials.

Now Washington is stepping forward with the "Access, Compassion, Care and Ethics for Seriously Ill Patients Act." Is Washington best suited to solve matters of morality and ethics?

Thursday, December 18, 2008

An Example of What is Not Innovation -- Uncontrolled Outsourcing to India

A frightening article, one that should be a wake-up call to those quickly outsourcing trials to BRIC (Brazil, Russia, India, China) without ensuring adequate controls:

The Latest Industry Being Outsourced to India: Clinical Drug Trials
-- From the St. Petersburg Times

Wednesday, December 17, 2008

All Knowledge Begins With The Beginner's Mind

I recently hosted a meeting of several international key opinion leaders representing a number of innovative technologies with applications for drug development. One spoke to a clever computer algorithm – an artificial neural network – that was being used for clinical purposes (as an example, identifying patients likely to develop Alzheimer’s Disease).

If you are not familiar with neural networks, then you may want to turn elsewhere for a primer (as I am hardly an expert). What I will say is that these are computer programs designed to act like the human brain and adapt – or learn – as they are shown more data. In the example above, show the algorithm more patient cases and it will be increasingly likely to predict who would get Alzheimer’s.

The speaker then showed a slide entitled “Over-Training”. In over-training, if one shows the computer too many cases they actually can start to see error rates increase. To be honest, I tuned out much of the conversation after this slide. I became fixated on the concept that over-training does not cause a plateau in the error, but that too much training actually causes more mistakes. The system becomes overly focused on individual cases and can no longer see the big picture.

Artificial neural networks were designed to mimic the construction of the human brain and our neural networks. But what can we learn from the lessons of over-training the artificial system?

Can we be over-trained? If we see too many cases or focus too sharply on one task, do we lose the ability to see the big picture? If so, how can we innovate and advance drug development? Are those on the “inside” too narrowly focused – and over-trained?

Expertise can be of value – but perhaps all knowledge being with the beginner’s mind.

Consortia -- Pre-Competitive Is In the Eye of the Beholder

It is hardly news that drug development is high-cost and high-risk. What is relatively new is for pharma to lower their guard and begin to share information that action together that may potentially reduce cost and risk. Enter the era of the pharma industry consortia.

Perhaps the grandparents of this space are groups such as the Biomarkers Consortium and the SAE Consortium. The C-Path Institute was created, in-part, to create consortia to act upon the FDA's Critical Path Initiative. Where there has been a lack of sound business models for creating new tools for drug development, consortia have been a good solution.

The ability for otherwise competitors to suddenly collaborate is based upon what some have called the “pre-competitive space”. At least one group has defined this as “technologies that aren’t really the basis on which they are competing but helps them do their jobs.”

But there is an inherent conflict. By their very design, consortia are meant to be inclusive and bring representatives from various related areas around the table. But what is pre-competitive to one stakeholder is likely a key revenue source, business opportunity, or competitive differentiator to another stakeholder. In most cases, “pre-competitive” is in the eye of the beholder.

Today it seems not a week goes by without another new industry-wide initiative being launched. Each requires an investment of resources and a commitment to see value ultimately generated.

Impact on drug development? Consortia have emerged as important mechanism for improving the clinical development toolbox (biomarkers may be a good example). But each initiative must start with an honest discussion among stakeholders around the table about what is truly pre-competitive, and whether everyone sees the same opportunity in the same light.

Dude Where’s My Bailout: US- and UK-biotech edition

This was going to be a posting a few weeks back when the US automakers were heading (back) to Washington in search of billions. Unlike the Wall Street package, most believed the financial struggles from Detroit were based only in-part on current economic turmoil and largely based on a flawed and unsustainable business model.

And so I penciled a what-if posting about pharma heading to Washington. Sure the largest players in the industry are sitting on billions in cash, but the coming struggles are well-known as some will lose over 40% of their revenue over the next 2 years with key products coming off-patent. Could they get in line for a bailout?

But before I could get back on-line and move from pencil to keyboard, BIO beat me to it.

Despite the headlines, the BIO request is perhaps more a cash-advance than a bail-out. Currently companies can use today’s operating losses to offset future taxes when they are profitable. The request in Washington is to let companies receive money from the government today in exchange for giving up those future tax deductions.

And BIO cites a direct linkage to the financial crisis – lack of access to capital coupled with roughly 25% of publicly-traded biotechs having less than 6 months of cash equals an inability to fund expensive clinical trials (or even stay afloat altogether). As the NY Times article notes, “the change, if Washington approved of it, could enable the industry to receive potentially hundreds of millions or even billions of dollars, on the condition that the money would be used for research and development.”

Meanwhile, a similar story from the UK -- although here perhaps more of a bail-out compared with a tax reshuffle. As proposed, first there would be a £500 million ($740M USD) government fund set-up to support consolidation among smaller biotechs. Then there would be a £100 million ($146M USD) VC-backed fund to enable larger biotechs to pursue acquisitions and fund clinical trials.

Impact on drug development – Increasing the potential for companies and trials to survive the economic chaos...especially as proposals in the US and UK stipulate applying funds toward R&D.

Friday, December 5, 2008

More attention in the news: Health2.0 Patients as Partners

Health 2.0: Patients as Partners -- at BusinessWeek.com

Media attention around the potential for Research 2.0 continues to swell...

Wednesday, December 3, 2008

In the news: Patient-led drug trials defy medical establishment

Patient-led drug trials defy medical establishment -- at Yahoo! News

Whether or not the scientific and clinical communities accept the trend, Web 2.0 will continue to enable and empower patients to share information and initiate their own research. (Once upon a time the medical community also dismissed the role of the Internet for patients to find health information.) Can we take measures to strengthen the tools available to patients, to make their efforts in generating research data a source of value (rather than fear) to scientists and clinicians?

Financial Times: Goldman unveils plans for pharma research funding

Goldman unveils plans for pharma research funding -- at FT.com

Interesting and creative new model proposed for managing both cost and risk in drug development. Will it work?

Monday, November 24, 2008

Economic Realities Continue to Hit Biotech Development

"Unprecedented" Biotech Bankruptices Erupt Amid Financial Crisis -- at Bloomberg

Biotech Firms Face Cash Shortage -- at USA Today

More Biotech Bankruptices on the Horizon -- at Fierce Biotech

Zagats for Clinical Trial Sponsors and CROs

Living in Manhattan years ago, Zagats defined how we found restaurants. This was Web 2.0 before the Internet -- relying on feedback from other diners to find the "best" restaurant.

Today the spirit of user ranking and feedback defines Web 2.0 -- TripAdvisor tells us which hotel is best, Epinions which product is best, etc.

We are also seeing the Zagat spirit in healthcare. Enter your doctor's name in Google and the first matches are likely all physician and hospital rating sites -- HealthGrades, Vitals, RateMDs. Even Zagats has entered the fray of rating doctors.

So how far could we be from sites where investigators and patients can post reviews and rankings for clinical trial sponsors?

Some groups such as CenterWatch have a history of surveying sites to identify top rated CROs and sponsors. But moving from a controlled survey to the "wild west" of Internet reviews and postings will be a different world. Same too for inviting feedback from patients.

If this seems unrealistic, that is probably what the venture capital community used to believe. No entrepreneur would ever dare to post ratings and reviews of interactions with VCs while seeking funding? And then came TheFunded.com, disrupting and nudging a long-standing power balance.

Today many are addressing the shortfall in number of investigators by looking for sites around the world, and addressing the challenges in patient recruitment by increasing trial-related advertising spend.
Perhaps such a review website would be good for drug development -- a site where investigators and patients were posting their feedback and ratings may force the industry to identify and address the roots behind the problems.

Freakonomics of Drug Development

In their best-selling book Freakonomics, Levitt and Dubner look at the world through the lens of economics and demonstrate how incentives (how people get what they want or need) are the root of most everything around us.

So what are the Freakonomics of drug development? Where are the incentives?

Here is a good starting question -- If you work at a "sponsor" is the goal of your company to make medicine or to sell medicine?

I would argue that if you are at a start-up biotech, you are there to make medicines. Your company likely aspires to get a drug into clinical trials, but it is unlikely they would still own the drug by the time of registration and equally unlikely the company would transform into sales & marketing.

If you are at a large pharma, I would argue your company is there to sell medicine. To confirm this, look no further than the revenue cliff ahead for most pharma as patents expire. The anticipated drop in sales is what drives most current decision-making.

So where are the incentives for those in development? Does your company reward for new project starts (regardless of ultimate project value)? Does it reward for killing a project early? Does it reward for innovation and risk-taking?

If your company is ultimately seeking to bring new approved medicines to patients and the marketplace as quickly and safely as possible, it would seem most of these incentives are misaligned.

Monday, November 17, 2008

Web 2.0 … Health 2.0 … Research 2.0?

Web 2.0 showed us how social networking, communities, and collaboration could make the Internet a more engaging and interactive experience – think Facebook, Flickr, and YouTube.

Health 2.0 takes a page from the Web 2.0 playbook to enable the health consumer (formerly known as "patient") to also become engaged in their health and wellness. Here we have on-line support groups and condition-specific forums. We have our health information becoming accessible with tools to make it actionable (via personal health record offerings from
Google Health, Microsoft HealthVault, and others). We even have on-line forums for medical professionals, enabling physicians to have peer-to-peer social networking (Sermo).

Health 2.0 brings great potential for improving individual wellness as well as public health, but what are the implications for clinical research? Should we anticipate “Research 2.0”?

In its most primal form, Research 2.0 could mean new ways to find patients that may be interested and eligible for clinical trials.
Inspire builds strong on-line communities of patients around specific conditions and diseases, then makes clinical trial matching available to these communities.

At another level,
PatientsLikeMe.com has demonstrated the willingness of patients to share personal health information and experiences for the benefit of their patient communities. Registered users (and there are several thousand) share functional status, medication and supplement use, and other interventions. As a result of this information sharing, PatientsLikeMe has found a novel Research 2.0 tool – patient-initiated research.

The patients in this community wanted better data to understand if
Lithium is of benefit to patients with ALS. In the spirit of “Research 2.0”, these patients are now sharing their experience – via structured, quantitative data – and creating a dataset including the clinical experience of several thousand ALS patients.

A future with Research 2.0 brings opportunity and risk. Patients may be recruited for trials through communities, but patients may also freely create a discussion forum within a community to discuss experience within a particular trial. Imagine a significant percent of the subjects in your randomized and blinded trial virtually “talking” with one another and exchanging experiences and observations. This is a reality one needs to anticipate.

Physicians have long been concerned about Web 2.0, with patients seeking health information on-line and the risks of user-generated content. But there is more to worry about than whether
Google can get a diagnosis correct.

Pharma has its own fear of patients in a world of Web 2.0, with concerns over inappropriate identification of safety signals (FYI, any known adverse experience linked to a specific drug that can be traced to an identifiable patient with an identifiable reporter
must be reported to FDA).

The dialogue can not be stopped, and so risks (and potential benefits) must be understood. Some (
see BMS and Novartis unrestricted grants for social networking) are already seeing this potential . Our patients are talking and the waiting room chatter is now global – are we ready to listen?

Images: Flickr

Will Change in Washington Bring Change in Clinical Research?

On January 20, 2009 change will come to Washington. Will a new resident in the White House have implications for drug development? Here are a few areas of possible impact:

Investments in Health Information Technology
Both Obama and McCain featured increasing investments in Health Information Technology as part of their healthcare reform proposals, and the recent Max Baucus reform proposal continues the trend. While the intent from the politicians is to decrease medical costs, reduce errors, and improve quality, there is great potential for clinical research as a by-product. The proliferation of electronic medical records and personal health records can bring transformation in the conduct of clinical research -- new opportunities to find patients, integration of EMRs and electronic data capture (EDC), running virtual trials, identifying biomarkers, the list goes on.

Personalized Medicine
Obama demonstrated awareness of the potential for personalized medicine back in 2006 when he introduced the Genomics and Personalized Medicine Act. And while the act never became law, the passage of GINA earlier this year did bring some protection around the use of genetic information. Outgoing HHS secretary Michael Leavitt has left a note to Obama emphasizing personalized medicine as a potent tool for repairing the healthcare system, which should be a good reminder to the new president that there is still work left undone. Increased investment in personalized medicine will bring more companion diagnostics into clinical development with each new drug, affecting everything from sample size to study logistics.

Continuing Focus on Drug Safety
Most feel the pendulum has swung and the FDA is focusing on safety over accelerating drugs for efficacy. With the media focusing on everything from safety of drug imports (including ingredients used to manufacture drugs) to what seems like every anecdotal report, there is no sign of this trend changing. For clinical development, sponsors will continue to aspire to accelerated approvals -- but will plan for the realities of studies large enough to demonstrate safety (to prove that every needle has been found in the haystack).

Beyond Safety and Efficacy -- Comparative Effectiveness
Once upon a time it was sufficient to run a development program to demonstrate safety and efficacy. Lessons learned from the UK's National Institute for Health and Clinical Excellence (NICE) have taught us the future adds a third endpoint -- comparative effectiveness. In fact, recent healthcare plans in Washington suggest creating an independent "Comparative Effectiveness Institute" for the United States, tasked with head-to-head comparisons of quality and cost for one drug vs. another. Be sure to have a few more voices at the table when writing that next registration study protocol (outcomes research, evidence-based medicine, etc).

Autism and Vaccine Safety Research
Obama and McCain were both enjoying the response of crowds on the campaign trial when raising the potential link between autism and vaccines. Assuming this campaign themes travel from Chicago to Washington in January, there is certainly the suggestion of additional research for vaccines new and old.

Stem Cell Reversal
Most seem to be anticipating an Obama reversal of the Bush restrictions on stem cell research. If this happens and if this research is successful, it would still be several years before one would see any heightened impact of stem cells in clinical research. But clinical trials of stem cells would certainly bring heightened planning -- from dose setting to safety monitoring.

New FDA Leadership
Other far more qualified political sources have taken educated guesses at naming the next FDA commissioner (including Scientific American's proposal of Stephen Colbert). We will need to wait and see in a few weeks, but the new leadership will certainly be expected to bring change within the agency -- which in turn will bring it's impact on clinical research.

Doing More with Less (and less and less...)
We have heard it time and time again. Big pharma are being hit by loss of patent protection to generics coupled with a weak pipelines and the growing risk of reimportation. And now small biotechs are expected to see challenges in raising capital to maintain their development work due to the credit crisis. This conspires to mean a familiar message for clinical development -- the need to do more (more products, more trials) with less. Except the "more" seems to keep growing and the "less" keeps shrinking.

What will come to fruition? Time will tell. But at last check we still have an aging population
in this country, and plenty of unmet medical need to go around. (Personally, I am going to make sure I know what HIT, EMR, and PHR all stand for...)

Image: Flickr