Compliance Zen

Reimbursement: Plan Early

In an interview I did with Clinica in the UK (which they turned into an article "Device Reimbursement: Plan Early, Says US Compliance Consultant"), I made the case that firms need to incorporate reimbursement evaluation and assessments as early as possible, preferably toward the end of the preclinical stage.

Some points from the article:

• The sooner you can evaluate reimbursement potential, the better your return on investment in clinical trials
• Try to build a reimbursement evaluation into the stage gate review process for moving a new medicine from preclinical to clinical
• Early reimbursement evaluation allows you to determine what potential customers (prospective patients, physicians, hospital administrators, etc.) will need to see when it comes to efficacy and safety claims
• Early reimbursement evaluation gives you the time to better shape your marketing messages to different customers
• Early reimbursement offers you the chance to set better cost controls for production and the rest of development; it will hardly benefit you as the company if you are making a product that costs you more than you will earn back in reimbursement

Key tactics to help incorporate reimbursement planning early in development include stage gates, regulatory affairs road-mapping, and clinical regulatory strategic plans, all of which I discuss in detail in my forthcoming book, Get to Market Now!

Bringing in reimbursement considerations as early as possible in development help demonstrate an integrated, holistic compliance and development strategy - and show how compliance departments such as regulatory affairs and quality management drive value to a company's bottom line.  And that's what I call Lean Compliance.

Are you ready?

Can Charles River Retune its Preclinical Operations?

Today’s news that contract research organization (CRO) Charles River Labs will be suspending its preclinical operations by mid-2010 in hopes of a biotech recovery is being met with the usual hand-wringing about the state of the industry following the near collapse of the global financial system in 2008.  I look at this a bit differently.  This suspension is a wonderful opportunity for Charles River to come roaring back with preclinical services better attuned and better able to take advantage of cutting-edge medicinal product development techniques.

In my book, Get to Market Now (slated for a May 2010 publication through Logos Press), I argue that firms can be making much better use of the preclinical stage through techniques such as:

• Crafting a clinical regulatory integrated strategic plan
• Bookshelving of previous studies into large databases
• Mining the data of those databases as part of an extended literature survey
• Capturing the voice of the customer (e.g., physicians, prospective patients, etc.)
• Summarizing preclinical studies to include potential critical product quality attributes (CQAs) and a risk analysis
• Planning and undertaking Phase 0 feasibility studies

Charles River has a good six months to put in place a strategy that incorporates tactics just like these, and offering them to clients (something that will save their clients money and time as well).  If your firm already has a number of preclinical studies underway - or planned - consider any of these tactics to help you improve R&D productivity and speed time to market.  Recent FDA and ICH guidelines encourage the adopting of many of these tactics through the quality by design philosophy.  Firms that ignore all the new product development options available to them in the 21^st century in the preclinical stage risk staying back at the 1 in 250 success rate of the 20^th century’s preclinical stage.

If you’d like to learn more about these tactics and adopting them into your preclinical development efforts, contact me through my firm.

Have a different opinion?  Share it.

What I Like about NICE

After reading an interview with Kalipso Chalkidou, director of the international division of the UK's National Institute of Health and Clinical Excellence (NICE), I was reminded what I like about NICE:  its emphasis on trying to handle the cold realities facing us all.  NICE is not loved by the biopharmaceutical industry and I don't blame the industry - I'd be frustrated too if I spent an average $1.2 billion USD to bring a new product to market only to see NICE review it and say, "Naaaah."

Unfortunately, getting mad at NICE is not going to solve the issue.  And that issue is one that came up earlier this year when I spoke at an National Institutes of Health (NIH) function:  how to drive down medicinal product cost while improving innovation.

What I like about NICE is that it reminds me to keep myself grounded in the big picture when it comes to future drug, biologic and device development and trying to contain costs while improving innovation.

NICE reminds me that before I sink $1.2 billion into developing a new medicine, maybe I should find out what the market will bear first.  In other words, NICE reminds me to do my homework; that I can't just follow the science.  That I have to balance science with business; that there is, ultimately, no real difference between the need to balance the books of a business that makes medicines and the books of a business that makes toasters.  Both businesses need products that customers want AND are willing to pay for.

Sounds so simple until you realize two little hitches:

1. The toaster business owner knows his customer is either the person shopping for a home toaster or the person shopping for a commercial toaster (like in a cafe) - medicinal product companies worry about that toaster-shopper plus his/her doctor plus his/her insurer.


2. The toaster business needs to worry about the same regulations that a medical products company does with one difference:  regulatory health agencies (e.g., FDA, NICE, CHMP, EMEA, etc.) - no easy task there.

NICE, Innovation and Effectiveness

As many of you know, I'm working on a book for Logos Press on the role of regulatory compliance departments (Regulatory Affairs teams, Quality groups, Compliance officers, etc.) in fostering new medicine innovation, lowering costs, and improving marketplace success.

Inherent in product innovation is the ability to adopt tenets of new product development innovation like Quality by Design as early as possible in the medicinal development pipeline.  In other words, to know before you spend $1.2 billion - and preferably way before you spend even close to that - whether or not a new drug, biologic or device has a chance not only of FDA approval but of a good reimbursement rate.

As NICE shows us, getting your medicine approved by the FDA or EMEA as safe no longer equals getting your medicine purchased.  Your medicine has to be effective.  And people tend to measure tangible effectiveness (not just statistical significance) with something they know - their pocketbooks:  are they or are they not getting their money's worth?

NICE and Game Theory

If you like game theory - that cynical philosophy that says people tend to act in their self-interest - then you have to at least appreciate NICE.

NICE is simply saying, "Look, just as with all other things in life, so it is with medicines and reimbursement:  at some point, you reach a matter of dwindling returns.  We don't have all the money in the world to buy all the medicines in the world for each of us - there is only so much to go around."  NICE is trying to act in the insurer's best interest and the best interests of all the people covered the insurer (in this case, the UK government is the insurer).

And so we again come to what I like about NICE:  it reminds us to think about the big picture; to remember that ultimately medicine isn't just about curing disease and saving lives, it's about making those extra moments or months or years of life worth the medicine's expense.  It's about ensuring the self-interests of not just the individual patient and the biopharmaceutical maker are served, but so are the interests of all the other prospective patients, the interests of all the other insured, and the interests of the insurer.

My own career experiences and those of my clients over the years have shown that if you can simplify and streamline compliance while pushing innovative product development approaches like QbD upstream in your pipeline, you can, quite clearly, save at least 6% of your total budget and get a far better feel for how likely your product is to get a good level of reimbursement.

So...let's see, 1.2 billion dollars x .06 equals $72 million.  That's a good bit of savings.

The NICE Challenge

Rather than complaining about where NICE is drawing the line on one specific medicine reimbursement versus another, I see NICE offering a challenge to our industry:  Can we figure out how to consistently make those extra moments of life worth the cost of our medicines?  Can we figure out new medicines that help serve everyone's interests?  Can we innovate to save lives AND save money?

I think we can.  But we can't just innovate by following the science; we're going to have to innovate across the product lifecycle, from preclinical development to postmarket monitoring.

Are you ready?

PAT and Computer Departments

As the term implies, Process Analytical Technology (PAT) relies on technology to help bring biopharmaceutical and device factories into the 21st century.  For many, this means working with your information technology (IT/ICT) department.

IT/ICT Assessment

To determine how you can work with IT/ICT, you need to establish how effectively your computer department is operating:

• Is your IT/ICT group struggling with the day-to-day and barely keeping its head above water?

          OR

• Is your IT/ICT group making good progress on bigger picture projects and strategic objectives while meeting tactical project deliverables?

Fancy methodologies abound to determine this, but a quick way to get a handle on where your IT/ICT group falls in the continuum comes by asking one question:  what is the ratio of IT/ICT staff to non-IT staff?

Ratios at 1:40 and above typically imply a IT/ICT department focused on the day-to-day, with only minor progress on large-scale projects.  As a former CIO, I’ve lived in environments stretching from a 1:12 ratio to a 1:97 ratio.  Let me assure you – good service does not come from having smaller service departments … nor do good project results.  My “quick and dirty” ratio question – while not perfect – will  give you a good idea if your IT/ICT group can play a strategic project role or will have to be relegated to a more tactical level with a greater reliance on PAT vendors.

 

Technology Tool Selection

At some point in the project, you’ll be ready for automation.  IT/ICT needs to be brought in before you’ve made any choices.

Ask your IT/ICT department the following:

What is the minimum level of network technology required for any automation to hook up to the factory network (look for terms like “CAT6e” and “Ethernet” and “100Mbps”)?

·         These items must go into any spec sheet to review potential vendor products.

How do you plan to integrate the system into the network?  Do you plan to do it yourselves or have the vendor help?

·         Rarely will an IT/ICT department choose to do it themselves, but offering the choice shows confidence and trust in your IT/ICT colleagues as valued team members.

What would you like to see in terms of long-term maintenance contracts with various vendors?

·         This is critical for long-term cost control and maintaining a qualified environment.

Are there any technology initiatives involving the factory infrastructure we (and any PAT vendors) should be aware of? 

·         After you’ve bought the automation tools and signed long-term vendor support contracts is not the time to learn about the factory network upgrade project.

 

Bring in IT/ICT Early

Make sure to ask IT/ICT to the table early on in your activities; they may need to schedule significantly in advance to best to help you.  This is especially the case if you outsource your computer department.  Depending on the terms of your contract, find out from your Purchasing group if the contract will cover this type of work in the factory, or if you’ll need to carve out a separate statement of work and quality agreement.

Based on my experiences working up the ladder from the help desk to CIO, support groups always appreciate a friendly “heads up” followed by a bit more information on what might be required.  Judge what you will say based on your estimate of what stage your IT/ICT department is in.

An IT/ICT department that is making good progress on strategic level projects plus supporting the day-to-day may want to kick-off a project.  An IT/ICT department struggling to keep its head above waters just in the day-to-day maintenance and installation may not want more than a “heads-up” and a “we’ll keep you cc’d on the meeting minutes, but for now, we’re still a long way away.”  That type of reassurance will help you gain positive reactions.

Always insist on IT/ICT being part of your project; do not let IT/ICT run a separate, parallel project.  I cannot begin to tell you the number of times I’ve seen that “separate but parallel” approach fail miserably (download the PDF of my article Six Rules for Great IT Project Success from the Journal of Projects & Profits and The Independent).

 

Final Thoughts

Process Analytical Technology relies on automation technology and in-line sampling.  This makes it necessary to work with your IT/ICT department to ensure you get the biggest bang for your buck when exploring various pieces of equipment and toolsets.

Remember, however, that PAT is not just technology; if anything, the “T” for technology is really just a third of the overall PAT framework. The bulk of PAT is analysis, risk management, science, statistics, and process management.  The “T” in PAT is only automated tools that will help you do this work faster.

 

Have a different opinion?  Post it and help everyone improve.

Quality by Design Frequently Asked Questions

Whenever I speak at companies on how to adopt and implement Quality by Design – whether in preclinical, clinical, pilot manufacturing, postmarket, and so on – four questions consistently come up:

 

Is Quality by Design like the old "process validation"?  We do all this work and get nothing in return?

In 2008, when I, along with the FDA’s Helen Winkle and Moheb Nasr, spoke at the PharmaQbD seminar, Helen pointed out that Quality by Design is the first real change—from top to bottom—of how we develop, test and manufacture medicines in over 25 years.

Based on my experiences outside the FDA regulated industry (see my 2006  article, “Elucidation:  Lessons from the Auto Industry”), I anticipate the entire product lifecycle approach will be very different within the next 10 years in the biopharma sector.  No longer, will we just “follow the science” - the marketplace simply cannot afford it.

Quality by Design is ultimately about figuring out how to balance safety, efficacy and quality with our bottom-line realities.

 

Does the FDA require us to comply with Quality by Design?

FDA officials (Kim Trautman, Janet Woodcock, Moheb Nasr, and others) have repeatedly announced at various industry conferences over the past 2 years the need to comply with Quality by Design and other ICH guidance. I give attendees at my workshops a special FDA industry report I authored that contains specific recommendations from FDA officials plus my own analyses on how to smoothly translate these ICH expectations into your environment (you can get your own copy of “FDA Quality by Design Expectations and Modern Quality Systems” on the Cerulean website).

You should also review warning letter 320-08-01 (April 21, 2008).  On page two is a citation for lack of ICH compliance, “The ICH Q7A Guidance (Laboratory Controls, General Controls) states that appropriate specifications should be established for APIs, including for control of impurities.  Your firm failed to establish….”

The agency is not participating in either ICH or GHTF regulatory harmonization efforts out of the kindness of their hearts.  Expect to build quality into your medicines by design or expect to be out of business in the next 20 years.

 

In July 2008, the FDA published a call for participants in a Quality by Design pilot for new biotech products—I thought Quality by Design was only for pharmaceuticals?

The pilot submission program (Docket No. FDA-2008-N-0355) is an example of the growing convergence of FDA regulations that govern pharmaceutical, biotechnology and medical device firms. Officials have repeatedly stressed, since the publication in 2004 of the cGMP initiative for the 21st century, their desire to streamline all the regulations governing these industries into one set of “medicinal product” rules.

Combined with the FDA’s expectation (see my “FDA Enforcement Report 2008-2009” compliance report) for companies to adhere to the ICH, it would be fair to assume that the eventual single set of regulations will look very similar to the ICH and GHTF guidelines. Both the EU and Canada are on the same track and the FDA, EU and Canada just signed a joint inspection agreement.

 

Can Quality by Design help us  draw the line between R&D work and more formal preclinical design and development activities?

Answers on this question range from as late in the development and design process as possible (putting it very close to Phase I clinicals) to as early as permissible in R&D to avoid having to redo any tests for inclusion in an eventual submission.

Consider drawing the line using the patent application as the demarcation.  Formal preclinical design and development activities should start when you begin the patent application process for a product you intend to commercially distribute/produce or otherwise license. Consider drafting company guidelines on this with your legal counsel and an outside, independent expert to advise you.

For further details on preclinical development and Quality by Design, see my article, “Using Quality by Design to Define Your Preclinical Package” in the Autumn 2007 European Biopharmaceutical Review.

 

How can we stay current with FDA Quality by Design expectations and industry best practices?

In addition to regularly checking in on the FDA and ICH websites, you can also monitor a growing number of websites that publish some material (most of which is ad-supported or sponsored by multiple vendors that sell PAT technologies and consulting services).

For a vendor-neutral, more independent approach, consider subscribing to my monthly quality systems and FDA compliance newsletter, SmarterCompliance™.  I offer a free trial subscription with which you may want to test the waters.

 

Got any other questions on Quality by Design?  You may want to download my free PDF executive guide to the FDA’s Quality by Design.

Featured Reading: Design for Six Sigma

 

If your organization is Six Sigma focused, the new product development methodology outlined in this book is a necessity.

If you are not Six Sigma focused but are seeking ideas on how to speed your development and lower costs, consider reviewing and adopting some of the tactics in Design for Six Sigma .

And if you are looking for help implementing the FDA’s Quality by Design initiative, this brief book should give you much food for thought.

Broken into nine chapters, the book outlines the overall strategy for implementing Six Sigma in a product design environment.  Along the way, the most relevant tools and statistical methods are highlighted.

Every chapter ends with a concise “manager’s checklist” of the most important concepts from the chapter (something that I’m trying to adopt for the book I’m currently working on).  Other reviews of this book have focused on how it is not an in-depth resource on applying Six Sigma to product development; I rather like it's tight, summary points.  If you're looking for the textbook on Six Sigma and new product development, this is not the book; if you're looking for a quick refresher you can skim and look for specific techniques, this is perfect.

While most of the book is applicable to firms under US FDA or other HHS regulation, the examples are almost entirely drawn from the consumer products industries.  The usual suspects from any write-up on Six Sigma are all present—Motorola, GE, and so on.

All round, the Design for Six Sigma is a good read for any executive, especially those in research, development and commercialization.

Postmarket FDA Surveillance: The New Rules

Adverse events and recalls have increased over the past five years, leading the US Food and Drug Administration (FDA) to consider total product lifecycle in its analysis of product safety and efficacy information.

In other words, did the company developing the product in question take a Quality by Design approach?

 

Quality by Design and Design History Files

With my clients, I suggest adopting Quality by Design (QbD) as early as possible in the product development cycle, preferably starting in preclinical.  Earlier this year, I wrote a four-part series in my compliance newsletter on Quality by Design and collaborating with universities in preclinical, clinical and the postmarket phases; an excerpt has been published on PharmaQbD under the title Back to School: Six Ways Universities can Aid Quality by Design Efforts.

In the case of products already on the market, I undertake a retrospective Quality by Design review of the design history file to highlight relevant preclinical and clinical information to identify critical quality attributes (CQAs) that support the safety and efficacy of the product.

While such a post-approval, retrospective QbD effort might seem too little, too late, there are four benefits:

1.       Much of the highlighted information can be re-used as part of the next product or incorporated into a new iteration of the current product, saving money, time and effort;

2.       The QbD information can be summarized and used during periodic product reviews (such as in your quality systems management review) to demonstrate continuous improvement;

3.       The information gathered simplifies the assessment required when an adverse event occurs; and

4.       The information can be used to implement process analytical technology (PAT) to streamline production operations and cut costs, all while improving end-product quality.

Ideally, a retrospective Quality by Design survey also documents evidence of management’s determination to ensure the product’s safety and efficacy.  In the event of the worst case, a product liability lawsuit against the company, Quality by Design (whether retrospective or not) can help justify decisions taken.

 

Quality by Design and Product Liability

Encourage your legal team to view Quality by Design as a means to provide protection from liability in product misuse lawsuits.

Through this liability lens, your Legal department can join forces with Quality, Regulatory Affairs, and product development teams to implement a Quality by Design strategy that identifies, documents and tracks a new product’s safety and efficacy characteristics as it moves through the development and commercialization lifecycle (see my seminar, Introduction to Speeding New Drug Development with Quality by Design, for more).

Because liability often focuses on the condition of the product at the time it left the manufacturer’s control (e.g., into distribution), Quality by Design should be extended to identify and control risks stemming from packaging and labeling.  This will further enhance a company’s liability shield under product misuse cases.

 

Quality by Design and a Postmarket Matrix

One recommendation that consistently delivers results for my clients is the creation of a postmarket matrix—with attendant summary metrics—to track postmarket issues and patient complaints, whether they result in an adverse event report, a recall, or otherwise.

The matrix provides solid proof of:

·         Continuing concern for safety and efficacy;

·         Quality controls to incorporate into development of the next generation of the drug or device;

·         Critical quality attributes that can transfer from one product to its follow-on without duplicating work or paying for unnecessary testing; and

·         Potentially new critical quality, safety and efficacy attributes that arise over time (and thus can support additional claims).

Such a matrix can be a simple table, similar to the one used to record your preclinical literature survey results.

 

Final Thoughts

The proliferation of new medicines, devices and diagnostic technologies, combined with the increasing pace of globalization, will continue to force the FDA into relying upon postmarket surveillance as a cornerstone of public health.

Retrospective Quality by Design can help you stay out of the spotlight and the courtroom.

Are you ready?

Internal Quality Audits as a Competitive Advantage

Most quality system internal auditors mistake their core role as verification of policy and procedure implementation.  As a result, the business never gets to take advantage of the most powerful capability of any FDA quality system:  improving product quality to a level noticeable by the consumer (and the regulator).

The simplest way to encourage both a standard operating procedure (SOP) audit and a consumer-oriented quality review is to design a set of tests or internal audits centered solely on the product and its relationship to the consumer.

In this context, rather than assessing if the procedure has been followed, the auditor looks at the product’s quality itself as perceived by a hypothetical customer.

 

Build Better Medicines

The core value of this focus shift is its end result:  better quality results in the lab, in the design phase, in the  prototype phase, and in final production; in essence ... you're testing to ensure you’ve built quality into your medicine all along the way from conception to distribution.  In other words, did you or did you not adopt Quality-by-Design?

Craft a single checklist of consumer-oriented product quality components that are tested all along the path of the product’s design, from start to finish.  For instance, you might examine the fit and appearance of seams in a device's hardware.  If the engineers and assemblers followed procedures, seams should be near perfect; if the seams and welds are sloppy, then you know someone didn't do his / her job.

In this way, you help force a better product and a patient-oriented quality system.

 

Test Continuously

Automate the tests by looking for common features that a computer program can test.  For example, with design files, look to ensure that all the corner points of the drawing meet; with formulations, verify the compounds, ensure that the molecule sizes are within  range and that the viscosity meets target parameters expected by the final consumer.

Once you have a standard battery of tests, you can automate them and gain the zero-cost efficiencies.  At that point, there is no good reason not run them frequently.  In the case of medical device software, thousands of test scripts can be run for several hours every night with the results waiting for you in the morning.

 

Resolve Problems Cheaply

Most drugs have side effects, most medical devices have drawbacks, most production processes have problems.  The questions are:

·         which do you know about?

·         when do you find them?

·         how much will they cost to resolve?

As a general rule, the more you test regularly, the sooner you find problems, and the cheaper they are to resolve.  The “surface area” covered since the last testing will be small, the number of areas to examine will be limited.  This is particularly critical as your design evolves and progresses.  You want to be able to rationally limit your impact assessments whenever you make an adjustment or fix.

You can also use these tests to revisit on-going high-risk areas to ensure risk-mitigation controls function as expected.

 

Control Flexibility

Many quality professionals like the consistency provided by SOP-focused audit.  Yet SOP controls often fly in the face of the cultures of scientists, engineers, and designers.  Because you’re more concerned with the end product and its impact on the consumer, with consumer-oriented testing you allow for a balance between control and flexibility to built into your SOPs and your audits.

By utilizing repeated, automated testing, your teams will move faster as they are able to test out new ideas and changes, respond to market changes quicker, and provide a stronger end product.

 

Make Consumers, Investors and Regulators Smile

Testing results can be shown to your investors, directors, consumer focus groups, and even clinical trial investigators.  Every company has a quality manual, but how many have regular testing routines and results all along the product path?

Continuous testing and improvement will give individuals comfort in your company, your product, and your controls.  That comfort will translate into higher revenue for you.

 

Share your better way to start turning compliance into competitive advantage….