Compliance Zen

Data Mining and FDA: What's Missing?

The FDA recently awarded Johns Hopkins University a three-year contract to develop advanced analytical strategies to mine the data residing within multiple FDA databases.  The goal is to find ways to allow drug and diagnostic firms access to anonymous premarket data (from submissions, failed clinical trials, etc.) related to safety and efficacy for specific patient subpopulations.  The project will, as FDA's Dr. Seyfert-Margolis notes, allow the agency to use "data mining with an eye towards sub-stratification of patients for efficacy and toxicity predictors."

Meta-analysis and data mining is actively encouraged in other product development fields outside of the life sciences. New product development specialists even have a term for such endeavors, "bookshelving." The intent is to flag previously gathered data from past products, experiments, failed innovations, consumer feedback, and so on, in order to take one of three possible actions:  skip portions of the development process, avoid dead-ends, or better target a product toward a specific set of consumers. In my book, Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine, I walk readers through how to incorporate this type of meta-analysis and data mining in preclinical and clinical development, as well as include it in quality by design implementation and submissions.

A study published by the Tufts Center for the Study of Drug Development found that less than half of pharmaceutical and biotechnology firms today are pursing personalized medicine projects in their pipeline. Given the slow - admittedly steady - progress of the FDA to publish guidelines associated with various aspects of personalized medicine development and commercialization, it is a testament to the industry's belief in personalized medicine that so many projects are underway without firm FDA rules in place.

Unfortunately, FDA's contract with Johns Hopkins University does not also cover all the postmarket data in FDA's possession.  While some postmarket data is available already publicly, there is little doubt that the agency has access to a great deal more.  And to realize the greatest return on investment in data mining, bookshelving and personalized medicine development, as much data as possible needs to be included in any meta-analysis.  Forcing firms to seek out other individual postmarket databases will not only slow their meta-analysis, it will jeapordize the integrity of any results.  Afterall, what if the one postmarket database containing critically relevant information is ommitted from the data mining? How will firms know?

Until the FDA can make all of its premarket and postmarket personalized medicine-related data available, firms may need regulatory affairs data specialists, adept in finding, collating, synthesizing, analyzing data across multiple sources - but do such experts exist?

Personalized Medicine and FDA Dance Closer

FDA has taken several more steps toward a 21st century regulatory framework overseeing personalized medicine. In April, FDA's Elizabeth Mansfield confirmed the imminent publication of a draft FDA guidance on the development and labeling of companion diagnostics.

The FDA guidance will require firms to validate a diagnostic test - or verify its compliance with a similarly approved diagnostic - before its use in a clinical trial associated with its companion drug. Such validation will need to include verifying the intended genetic sub-population and the diagnostic's ability to consistently and accurately assess the sub-population. The label of the diagnostic will also need to specify its companion drug.

While some in the industry argue that diagnostics should not be tied to specific drugs, experience with Roche's drug Herceptin has encouraged FDA to push for firms to indicate, at least initially, the specific drug for a new diagnostic. In this way, the agency hopes to encourage drug and biologics firms to partner with diagnostic makers as early as possible, preferrably during Phase II clinicals of the new drug.

This emphasis echoes an argument made in Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine:  that over the next ten years, companion diagnostics will play the leading edge of mainstream personalized medicine.

The agency is steadily pressing the development of regulatory science to meet the personalized medicine evolution. If you've not already visited and bookmarked the FDA's genomics section of its website, I encourage you to do so. The information can help you determine the specific genomics information the FDA wants to see in a submission. This, in turn, can provide valuable reverse engineering insight for planning clinical trials and even companion diagnostic partnerships.

Back in early 2010, I wrote an article for BioProcess International entitled Building Compliance for Personalized Medicine, about the internal compliance frameworks that companies need to be establishing to stay ahead of both the FDA and the personalized medicine curve. The advice within the article is just one set of regulatory intelligence that regulatory affairs and quality system executives and professionals need in order to plan and succeed in the decade ahead.

If you'd like regulatory affairs expert or quality systems expert help in setting up a 21st century regulatory intelligence program, contact me today.

Cost of Drug Development Criticized

The journal BioSocieties has published a study critical of the cost estimates of new drug development used by PhRMA and the Tufts Center for the Study of Drug Development.  The article, Demythologizing the High Costs of Pharmaceutical Research, notes that PhRMA and Tufts claim costs 18 times higher than those analyzed and verified by the authors:  $43.4 million versus Tufts' $802 million and PhRMA's $1.3 billion.

While perfectly accurately costs are unlikely to ever appear without an international, agreed-upon set of "R&D accounting standards" followed by completely open books at thousands of small biotechs and Big Pharmas around the globe, the new medicine cost trend is clearly getting worse.  But is cost the *real* issue?

Some key facts (from Is Quality by Design Right for My Organization?):

1. The average time to market for a new biologic or drug is 10-15 years (1-2 years for discovery, 3-6 years for preclinical, 3-6 for clinical, 1-2 years for review and approval)
2. Only 8% of new biopharma compounds ever make it to market
3. Less than one-third of all approved new drugs ever recoup their investment costs
4. And once a generic hits the market, revenue from the drug declines 80%

So let's put this all in investment terms.   Pretend I want to offer you stock in a new company I'll call "Miracle Drug Inc" (MDI).  Now, there is only an 8% chance of this company (and your investment) surviving more than 10-15 years.  Would you like to invest?

Well, what if I told you that IF MDI survived, your stock will only have a 30% chance to be worth as much as you invested or to make money?  Otherwise, you have a 70% chance to just lose money.  Still want to invest?

And what if I told you that 8-12 years AFTER your stock actually broke even or made money, it would - guaranteed - lose 80% of its value (and never recover).

Which would give you a more reliable return-on-investment for your money?  Investing in MDI and its new miracle drug or hiding your money under your mattress?

This is the real problem - not whether it really costs $43.4 million or $802 million or $1.3 billion to bring a new drug to market - but how to improve the odds of success.  Ultimately, it doesn't matter how much a new medicine costs to bring to market as long as the company can make money.  But how many of us would give our money away with only an 8% chance divided by another 30% chance just to earn it back?

As I note in my latest book, Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine, there are really eight powerful factors underlying all of this, and cost is only one:

1. Healthcare Cost.  Let's be blunt:  with declining birth rates, aging retirement populations, debt laden societies, and struggling economies, Western countries cannot afford the best of everything any longer. And those patients in emerging markets - from Latin America to China and India - do not make up a wealthy enough consumer base yet to reliably provide the revenue Big Pharma (much less Big Biotech) has grown used to.  In other words, the industry is facing customers who cannot afford the latest and greatest products.


2. Knowledge Specialization.  In my lifetime alone, we've gone from just general toxicologists to neurotoxicologists to proteomic-neurotoxicologists.  Knowledge - and information - has become so complex, so focused, that I count it as a miracle every drug on the market isn't immediately pulled off as every day seems to bring a new scientific advance that questions safety assumptions we held even two or three years ago.  This means that putting together a development strategy is like assembling a puzzle that grows more and more pieces every time you sit down.


3. Virtual Companies.  The advent of the Internet has allowed more and more firms to operate without an actual headquarters, without a manufacturing site, and so on; it's all contracted out or doesn't exist.  In the real world, how do you ensure that your new medicine is being manufactured safely or its distributors are storing the medicine properly when your manufacturer or distributor has no physical presence other than a website?


4. Generations and Demographics.  Demographics are working against biopharma companies and will continue to do so for the next two decades.  It may seem that lobby groups like AARP and other senior citizen associations help advocate for new biopharma drugs, but then you have to look at the articles in their newsletters and magazines to see their ratings of Internet pharmacies to get drugs cheap.  And make no mistake, there is a growing knowledge gap as experienced regulatory professionals retire all over the globe just as biopharma demands cutting-edge, personalized medicine regulatory experience.  Think of it this way:  Is it easier to simply retire or to have to spend your last few years getting up to speed on this new thing called "quality by design" and how it relates to personalized medicine?


5. Rapid Rate of Technology.  Technology is a two-edged sword.  On the one hand, it's wonderful that biopharma firms can so rapidly plow through lab testing of new molecular entities.  Conversely, because of the rapid rate of technological advancement, two challenges occur:  first, automated testing puts people (i.e., future customers) out of work, and second, the regulations can't keep up.  For the former, if your customer doesn't have a high-paying job, he/she can't afford your high-priced products.  And when it comes to regulations - did you know that when FDA was starting to write 21 CFR 11 on electronic records and computer validation, ALL the computer power on planet earth was LESS THAN the power in today's iPhone?  'Nuff said.


6. Globalization.  Let's face it, we have supply chains that go around the world at least once.  And if I can buy a new medicine for LOT less over the Internet, why wouldn't I?  How long will it be before a service exists that conducts random quality tests on Internet-purchased medicines to provide a guaranteed level of purity?  And let's add to that the dramatic increase in medical tourism.  When it's cheaper for customers to fly overseas to get an operation and medicine than it is to get the products and services from the hospital and pharmacy 3 miles down the road, our business model is not on the right path.


7. Increased Compliance Burden.  This isn't about more regulations or less regulations; companies have been complaining about regulations since the days of Hammurabi.  This is about the fact that the more I have to customize, tailor and personalize my new products to smaller and smaller sub-populations, the more clinical trials I have to conduct, the more quality audits I have to undertake, the more CAPAs and complaints I'll have to deal with, and so on.  In other words, the regulatory affairs and quality system approaches of last century seem increasingly out of touch with today's needs.


8. Overly Rigid Quality Systems.  In light of all of the above, more and more SOPs and policies seem out of step with business requirements in the 21st century:  flexibility, cost efficiency, and real risk reduction.  My goal with my lean compliance workshops and consulting is to at least tackle and solve this one issue outright (much less try to walk professionals and managers through solving the other challenges associated with FDA, ICH and/or GHTF compliance).

These eight real challenges inhibit new medicine success in the life sciences today. Don't get sidetracked with just one issue. And while there are no easy answers, I've outlined 113 specific tactics that do work in my latest book, along with the examples and case studies that show why these work.

If you'd like to learn more about the book, the publisher is allowing free downloads of the first chapter.  You can download the first chapter free of charge at the book's website, http://www.Get2MarketNow.com.  The site has links for ordering, as well as reader resources such as downloadable checklists, templates, mini-tutorials, helpful links and so on.

I look forward to hearing your thoughts.

 

Pharma Regulatory Science - FDA, EMA, MIT, NIH - Oh My

Following the FDA announcement to work on pharmaceutical regulatory science with the NIH early last year, the European Medicines Agency (EMA) has announced its partnership with MIT.

Pharmaceutical regulatory science is a nice code phrase for building quality and safety into drug and biologics development from the preclinical stage on forward, even through the postmarket. This includes aspects such as quality by design, postmarket pharmacovigilence studies of aggregated healthcare data, and so on. In other words, everything I suggest to readers in Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine. Of course, the book only offers case studies and suggestions - recommendations that are slowly being turned into regulatory requirements.

In fact, in a recent story for Knowledge@Wharton, Wharton's business school publication, my book is mentioned as presenting a series of coherent strategies to help companies speed new medicines to market while staying within the bounds of FDA regulations, evolving science, and recent enforcement trends.

You can read the Wharton business school story here:  Road Blocks or Runways? Regulators Strive to Speed Drug Reviews without Losing Rigor

You can read about the FDA and NIH cooperation here:  FDA and NIH Announce Collaborative Initiative to Fast-Track Innovations to the Public

And the recently announced EMA and MIT collaboration here:  Joint EMA-NEWDIGS research project

Pharma Regulation - More on the Horizon?

If the FDA ever needed another reason to increase its pressure on pharmaceutical and drug firms, it's this:  a November poll found that the US public wants the pharma industry to have more regulation than the tobacco industry.  You read that right - the US public trusts the pharma industry LESS than the tobacco industry.  In fact, the poll found that the US public rates the pharma industry right up there on the trustworthy scale with BP and the rest of Big Oil.

The Harris Poll found that close to half of surveyed US adults want the pharma industry to have more regulation (compared with a little over a third suggesting more regulation for the tobacco industry). Only a 1% difference separated the desire for pharma to face more rules and scrutiny than the desire for Big Oil to face regulatory and Congressional grilling.

And let's face it, a large part of this negative perception is not going to be solved by FDA regulation - either more or less of it. The US public's negative perception of the pharma industry has a lot more to do with frustration around ever increasing cost of medicines than it has to do with whether more Codes of Federal Regulations should be written.

Another aspect to the "untrustworthy" label has to do with pharma's own gaffes such as GSK's ghostwriting of articles for the medical literature on Avandia, the court litigation over Paxil where GSK was forced to admit to ghostwriting articles that concealed the danger to children and teenagers, and the recent revelation that half of all articles that mention Zoloft were funded and ghostwritten by ... the maker of Zoloft. Who knew?

So what does this mean for FDA-regulated companies?

From the FDA, expect more aggressive enforcement by the agency of corporate executives who knowingly ignore or short-shrift compliance activities such as quality systems, an increase in FDA inspections, and the likelihood of more public transparency of FDA findings. Recognize that the agency will continue to scrutinize medical literature for its accuracy and integrity when articles cite specific medicines.

From the public, as I make clear in my most recent book, Get to Market Now! Turn FDA Compliance into a Competitive Edge, frustration with the industry will continue until industry adopts a cost-efficiency strategy to developing new medicines. I'm not talking about slashing payroll and leaving the remaining employees with the feeling they need to work 50-60+ hours a week to avoid their jobs being outsourced. What really needs to happen is a new medicinal product development methodology, from preclinical through the postmarket, that acknowledges a simple reality:  the cost of new medicines cannot continue going up and up and up in perpetuity.

I outline, and walk readers through step-by-step, a 21st century pipeline development approach in my book, something that every reviewer - including industry executives and former FDA officals -  has mentioned and loved:  those real, tangible, "here's what you do and how to do it" steps, plus all the examples.

Until such an approach is firmly in place across the industry, however, Big Pharma will just need to get cozy with their new best bud, Big Oil.

Does Drug & Device Efficacy Equal Cost-Effectiveness?

At the end of November, Michelle Andrews had a fascinating piece in the Washington Post called "Like a Lollipop at the Dentist's, but for Grown-Ups" (or Value-Based Insurance Design's Pros and Cons) wherein she discussed how companies are working with their insurers to provide 100% reimbursement for medicines known to be highly effective.  And not just drugs are reimbursed at 100%, but devices, doctor's visits, physical therapy, and so on.

The challenge for drug and device firms goes beyond simply FDA approval to achieving marketplace (or consumer) approval in order to recoup the millions spent on development.

With the UK's NICE getting ready to take a backseat to value-based pricing (also known as medicine efficacy = efficacy), the move by companies and their insurers to push employees (i.e., consumers) to more effective medicines, is another efficacy threshold test beyond just science.

And those companies banking on "developing markets" would be wise to be cautious.  As a recent Bloomberg news story, China Slashes Roche, Bristol-Myers Drugs to Pare Costs, makes clear, a highly profitable future does not exist in developing markets for new medicines.  These regions are especially price-sensitive with governments willing to enforce price controls to ensure social stability.

In the 2010s, firms that develop cost-effective drugs and devices see efficacy as speaking to the ability of medicines to be personalized, to use every means available (such as genetic sub-population profiling, quality by design, voice of the customer incorporation, and so on) to demonstrate to consumers that Medicine X is vastly more effective for you (the consumer) than anything else - and not just because of the science and engineering behind the product, but because of the quality built into the processes that control the manufacture, storage and distribution of the product; processes that ensure that when you, the customer, get the product, it will work 99.9% of the time the exact way regardless of what you ate that morning or if you're also on Medicine Y at the same time, and so on.

One of the points that readers and reviewers of the book Get to Market Now! have made over and over again is how the book walks you through how to personalize medicine (and add quality by design) as early as possible in the development pipeline stage.  If your company is trying to figure out how quality management systems, regulatory affairs, and R&D can all play well together, Get to Market Now! shows you exactly what you need to do - from preclinical through the postmarket.

And as is becoming abundantly clear - if a firm doesn't have a good strategy for ensuring cost-efficiency and efficacy in a product, marketplace acceptance ... or lack thereof ... will doom any chance for a positive return on the millions it took to get to market in the first place.

Pre-Informed Patients and FDA

In chapter four, "Larger Landscape Trends," of my book Get to Market Now!, I analyze the impact of the pre-informed patient, and the challenges drug and device firms increasingly face in the 21st century.

An October 5th Federal Register notice stated that FDA will conduct at least two national surveys to "assess behaviors and beliefs related to the use of medical products."  The surveys will also attempt to determine how the public perceive the credibility of FDA and other sources of drug and device risks and benefits.  In other words, the FDA recognizes that drug and device executives need to start incorporating Voice of the Customer from the pre-informed patient.

More than 60% of adults turn first to the Internet to conduct basic healthcare research on treatment options, drugs and devices, and even new medicines in development.  As Generation Y grows into adulthood, this percentage will undoubtedly increase to above 90% within the decade.  The challenge is that these pre-informed patients can either act as advocates for your new medicine...or can relegate it to the treatment of last resort.

Two months after my book's publication this year, FDA announced the agency would begin publicizing its postmarketing safety reports on the FDA website.  This new resource site for consumers and healthcare professionals should better help people make informed decisions about medicines on the market.  This FDA site already adds to those sites such as DrugWatch.com, RateADrug.com, and others.

For drug and device executives, however, more food for thought exists.  Thinking about how consumers and physicians will use the FDA site should generate many questions:

• What treatment decisions are prospective and current patients making as they become aware of this information?
• How is this information being handled in a social media context?
• Should a firm be letting FDA initiate this conversation such that the firm has to play catch-up in discussing postmarket safety concerns?
• What triggers should regulatory affairs teams be building into their regulatory strategies, clinical plans, postmarket studies and Phase IV trials?

Ironically, as I was writing my book Get to Market Now!, I sat in a client's meeting room and listened as a senior clinical director explained rather boldly, "Oh, we don't plan for postmarket studies and trials because FDA will never force us to conduct any."

"Perhaps," I remember thinking, "but then FDA doesn't actually buy your drugs - pre-informed patients do."  And when drug sales begin sliding from the dissemination of postmarket summaries and FDA treatment reviews - in combination with feedback on sites such as DrugWatch.com and RateADrug.com, etc. - my guess is that this director's firm will be hastily planning and conducting postmarket studies and trials while playing public relationship defense. In fact, agency officials have confirmed in private conversations that what is publicly posted on reputable internet sites about marketed drugs plays a role in agency decisions around requiring Phase IV studies and trials.

Rather than leave such initiatives in the hands of consumers and regulators, better, I would think, for clinical, regulatory affairs, and development teams to be proactive.

If you want to know how to turn the pre-informed patient to your advantage, check out the many 21st century drug development strategies and lean compliance tips in Get to Market Now!  You can get your copy from Amazon.com, Barnes & Noble, or direct from the publisher, Logos Press.

Cooperative Drug Development

Pfizer's recent pact with UC San Francisco is the latest in big pharma's move to the new collaborative drug development model that is part of the 21st century new medicinal product development framework that I lay out in my book Get to Market Now!

Using university labs to help transition from preclinical and Phase 0 studies into clinical trial is just one economical method to move from discovery to trial.  Done well, such partnerships can also speed time to market and increase the success rate of new molecular compounds.  In chapters five and six of Get to Market Now!, using case studies and examples, I describe specific tactics to effectively collaborate with universities:

• Literature surveys
• Compound optimization
• Formulation sampling
• Personalization target profiling
• Pharmacometrics modeling
• Preliminary adaptive trial design
• Pilot manufacturing optimization
• Labeling and packaging usability design
• Voice of the customer surveys
• Voice of the customer prototyping design groups

As a former FDA inspected noted about Get to Market Now! Turn FDA Compliance into a Competitive Edge:

Avellanet advocates that quality by design is not just for GMPs but for the entire life cycle of the development process. His book reviews step-by-step how to incorporate quality into the product development and post-marketing compliance standards.

- from's Carl's GxP Perspectives

Get to Market Now! is available from Amazon.com, Barnes & Noble, Borders Books, the Publisher, and other fine booksellers.

 

Postmarket Studies and Surveillance Requirements Increase

FDA's approval of Amgen's osteoporosis treatment, Prolia (denosumab), came with strings attached:

• A global long-term study of adverse events in women
• Continuous monitoring and post-market data collection and analysis
• Medication guides for patients
• Communication plan for physicians and healthcare providers
• Patients to therapy program

Much of this was encapsulated in a risk evaluation and mitigation strategy (REMS) negotiated between Amgen and the agency.

Postmarket surveillance requirements - including Phase IV trials and studies - are increasingly part of the FDA approval pathway in the 21st century.  There are a number of reasons for this, including:

• Explosion in scientific and engineering knowledge over the past decade
• Increasing complexity of technical and scientific equipment, techniques, and methodologies
• Growing body of inter-relationship or convergence of new bodies of knowledge and technology

All of these and more I lay out in my book, Get to Market Now!, plus a corresponding set of tactics and steps to take to minimize your risks and your costs.  Long-term, executives should expect that Phase IV commitments are simply part of doing business in the US and other ICH and GHTF member nations.  The sooner you can define postmarket surveillance components in your new drug or device development and commercialization plans, the better your chances of success and the lower your risks and costs.

Incidentally, this was the same conclusion that the Institutes of Medicines (IOM) acknowledged in its July report, Ethical Issues in Studying the Safety of Approved Drugs.

As readers and reviewers of Get to Market Now! have seen with my 21st century new medicinal product development framework, the days of drug and device development ending with the submission are over.  Are you ready?

Personalized Devices Call Doctor for Help - Is Anyone Listening?

A new crop of medical devices currently in clinical trials is bringing personalized medicine to a new level:  the devices send signals direct to the doctor's office about operational status and any alarm thresholds, much like data center computers that can send log files and alerts to IT network administrators.  Most impressive is a new heart implant that detects heart functionality, tells the patient how to adjust medication, and notifies the doctor of any changes.

The challenge, according to physicians, is what to do with the data gathered on a daily basis; ironically, the same exact challenge still struggled with by IT network administrators when it comes to computer log files with hundreds of daily entries.  It's a big, "Well...so what?"

In other words, beyond just information overload, physicians are facing data whose implications are unclear.  What do changes in thoracic impedance actually signal?  Even heart failure specialists note that variance in thoracic impedance can be really important...or utterly insignificant...all depending upon the context.

This cutting edge technology is seductive to medical device engineers at firms such as Medtronic and Boston Scientific, and why wouldn't it be?  But one of the challenges presented by these cutting edge devices is what to do with all the data?  Doctors wonder how liable they are if information from a device comes through and they have no idea what to do with it, or, during a harried day, can only spend a scant few seconds thinking through context and implications.  And the FDA and the FTC agree that they need to support telehealth innovations.

Device firms looking to push patients to supplement the transmitted device data with their own observations (e.g., "the reason my blood pressure is high this morning is because I had a bag of potato chips last night"), are facing challenges of how to get patients to tie personal observations to data collected in a timely manner, not to mention getting both physicians and patients trained.

But is all of this the right way to go about adopting such cutting edge technology?  To come up with the technology and the device first, and then figure out how to patients and doctors to adopt?

One of the tactics I walk readers of my book, Get to Market Now!, through is incorporating consumer feedback into early stages (preclinical) of new medicine design and development.  In new product development circles, this is known as gathering the "voice of the customer."

Seen in this light, including voice of the customer information in biopharma and device development is simply another aspect of good quality by design.  From my experiences and those of my clients, voice of the customer data can help reimbursement organizations - such as CMS, NICE, and private insurers - agree to higher levels of reimbursement.

To see specific examples and techniques of how to incorporate voice of the customer in preclinical, clinical and even postmarket activities, see the chapters on improving pharmaceutical innovation in Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine.  The entire second half of the book is dedicated to showing readers, step-by-step with examples and case studies, how to boost device and biopharma R&D productivity.