The Role of Key Opinion Leaders in Clinical Trials

A group of us were watching an American football game last weekend.  We witnessed a wide receiver catching a pass and proceeding to dance around, looking for an opening to run up the field.  He must have run 100 yards by the time that he was tackled – he looked exhausted, pulling himself out for the next play only to be met by a waiting head coach, screaming like crazy.  The player proceeded to lose yardage despite the fancy footwork and dazzling moves.  The announcer on the broadcast was silent for a moment, then made the following statement: ”Players learn in pee wee football that the goal is to run North and South, not East and West.”

This vignette brought to mind a recent study experience, where a biotechnology company with terrific thought leaders and Advisory Board contributors were implementing their clinical trial for a novel compound addressing an area of unmet medical need.  Technology was utilized to capture case report form data, randomize subjects, and integrate third party sources – all in an effort to continually clean the entries made by the sites and provide as comprehensive a report each month for all participants to review.  After the initial first pass of information was entered, a comprehensive review took place, which everyone enjoyed.  They scrutinized all of the information, evaluated the patients medical histories, etc.

The thought leaders noticed some interesting information, perhaps a trend, and inquired about exploring it further – they were held in high esteem in their field, and could heavily influence the use of this product if approved.  So, the clinical team implemented the changes, causing further delays in the study, causing major changes to the database, and leading to additional time and cost impacts.  Upon further review by the clinical team, it may have been good information for a publication by a thought leader, but had no impact on the primary and secondary endpoints – the goal for the study.

So we see evidence here of the relationship to our wide receiver, maneuvering their best to gain more yardage when just turning and running up the field would have been the more obvious choice.  Key Opinion Leaders (KOLs) fill a needed and valuable role in designing protocols, answering medical questions, review and analyze data, and interact with key investors to confirm the commitments to the trial and its benefit to patients.  Their input during the course of the trial should be assessed on its impacts to the key goals of the study and direction of the program. 

Granted there are many great ideas and thoughts provided by KOLs, no doubt.  But will they lead us “North and South” or “East and West”?  Some suggestions may be better served as Investigator-Initiated Research studies to allow further evaluation and possible publication, maybe some offer thought-provoking discussion that can be further evaluated at a later date.  In all, the focus on the endpoints and the goal line will help to keep you running North and South, getting ever closer to the ultimate goal – an approval.

Effectively Managing Your CRO - Establish A Solid Blueprint

Before you build that new home or put an addition on your house, you sit down and sketch out a variety of looks and features that you would like to have included in the project.  You take your notes and prints to some area contractors and ask them to propose upon your project.  In some cases, you learn that the project is within your budget, or some sacrifices have to be made to meet those budgets.  Then, the work begins.

During the project, you find out that an allowance was included for your bathroom fixtures which is something above the least expensive item at Home Depot; you learn that the budget proposed a certain number of light fixtures which falls far short of your expectations, so this is added.  You learn that your measurements are off just enough that you now require an extra piece of granite to be purchased for your kitchen island.  What went wrong?

There are often many references made to the construction industry when speaking about clinical trial execution, but arguments from both industries are very similar when it comes to identifying your plan, whether it is a blueprint and specifications book or a protocol and defined vendor agreements.  If the protocol is cut and pasted, or it is something that was constructed 10 years prior using out-dated procedures, you will find challenges and difficulty in executing your program, regardless of your vendor choice.

The basic tenets of writing a protocol – the regulatory input, the identification of primary/secondary/tertiary endpoints, etc. – are understood.  A few additional considerations can help to ensure that you have the appropriate detail and information to lean on a well-constructed protocol to guide your service providers:

1.  Be sure that the protocol considers Standard Of Care practices.  Our team has been involved with two studies that exceeded the Standard Of Care practices in the field.  In both situations, the trial proceeded forward despite many physicians not allowing patients to use higher doses of toxic drugs or allow patients to reach measurable levels of disease that exceed protocols of many healthcare organizations.  In many cases, across international lines, the standards of treatment can vary from country to country.  Consider the field conditions when developing your program.

2.  Be certain that physicians can actually identify subjects who match your needs (feasibility).  Site selection is continually a challenge; physicians want the business and their teams feel that they can recruit the required number of subjects, yet 70% of sites fail to meet the minimum accrual requirement.  Canvassing treating physicians to review your protocol is one way to ensure that the procedures referenced are current, patients do fit the profile required and the sites can be successful when engaged.  In addition, there are services that will mine databases to locate patient pools and validated physicians to further validate the protocol and identify areas that have patients to support your needs.

3.  Ensure that patients who exist will want to participate (viability).  Many protocols include a variety of tests, blood draws and data collection that impede on a patient's quality of life.  In addition to ensuring that sites see the appropriate patients, a consideration is strongly suggested to inquire with patients who have the condition to determine if they will comply with the requirements of the program.  In addition to site selection, patient compliance is also a great challenge for sponsor companies.

4.  Walk through the logistics of the program to identify any outliers in terms of service support.  Your program requires interesting logistics around sample collection, and it is assumed that your CRO partner has addressed it.  But, they have only budgeted for the basics of sample handling while your requirement is much greater and more involved.  Working out the logistics of the entire study with each participating functional area can help identify some areas of challenge that should be discussed proactively and addressed in the timeline and budgeting process.

5.  Be sure that your selected CRO partners have an opportunity to contribute enhancements.  CROs, whether full service, or functional/specialty blends, have a wealth of experience and history.  Many of these people have had experiences across multiple programs in similar areas.  If they have the experience, use it - get it during your protocol development or during the logistics discussion.  It is one of the reasons that you chose your partner, so get them involved - it will also help them provide a better service if they are making suggestions to enhance the study.

"A Small Fish In A Big Pond" - Effectively Managing Your CRO

OK, the decision has been made to downsize your organization, or to remain steadfast with your core team concept, and your company opts to select a Contract Research Organization (CRO) for your clinical development support.  And why not?  They appear to have all of the services covered, skill and experience, and in some cases, global operations appear to be synergized under common SOPs – I mean, you met their management and operations team during the bid defense and their team was stellar.

So, months pass following the contract award:  the scope of the project may have shifted triggering a flood of change orders from your new "partner", the contract team seems to be different from those who bid on the project - in fact, they are less experienced and skilled, and the access to senior level expertise to guide your decision-making doesn’t appear to be as readily available as initially promised.  What happened?

In many cases, the challenge lies with both the sponsor and CRO company when the relationship is formed.  Small to medium-sized companies are being pressured to prudently manage their resources ($), and a similarly valid argument can be made for larger pharmaceutical companies based on current trends.  The expectation of the full service CRO is to deliver the projects on time, on budget, and of high quality – as if they were a true extension of their sponsor partner.  More often than not, there are unmet expectations and failures to deliver due to a variety of circumstances.

Recent articles in Outsourcing-Pharma.com highlight trends in the industry regarding large pharma/CRO relationships.  One discusses that a bulk of a larger CRO’s revenue come from larger pharma clients, while a separate article indicates that 12 of the Top 20 pharma companies will utilize outsourcing 100% of the time.  Given this dynamic, the small to medium-sized sponsor companies offer very little in terms of backlog to the CRO, plus create even greater challenges because of the “hand-holding” required due to limited sponsor resource.  For the CRO, it is understandable that the larger clients get more of the attention – the larger pharma companies have pipelines, money and keep people at the CRO employed.  This is just business.

But for the small to medium-sized client who has investor money and personal investment in their projects at stake, time and money are of the essence.  So one wonders how these small to medium-sized companies can be more effective in using their selected partners, and ensure that performance, timeliness, and quality are being maintained on their projects?  The FDA continues to increase staff in order to focus on sponsor companies and their use of external providers, their oversight and compliance with regulations – after all, it is the sponsor is held responsible and accountable for the conduct of their studies.

The solutions to these scenarios reside in not only the planning stages, but throughout the life of the relationship with the CRO.  Consider the following opportunities:

1.  Establish a solid "blueprint" with a well-written protocol

2.  Select the appropriate CRO

3.  Establish well-defined Service Level and Quality Agreements

4.  Include qualifications of your key contacts at the CRO company in your agreement

5.  Establish an oversight team to ensure performance and quality

6.  Ensure that your corporate standards are being utilized

7.  Leverage technology and study reports for more effective management

These are a few simple ways to ensure that working with your CRO partner can lead to successful clinical trials.  Outsourcing of development resources continues to increase throughout the sector and, as more companies lean towards the use of larger, established CRO companies, the more necessary it becomes to ensure that your program receives the proper attention.  In addition, it enables your core team to consider the kinds of companies and partners that will complement your internal staff.

Creativity and Innovation in the Outsourcing of Clinical Trials

I recently attended the Elsevier Business Intelligence Conference in New York City which gathered a group of industry thought leadership from large pharma, biotechnology, medical device, venture companies, consultants, payors, etc. to discuss Strategic Alliances and the challenges which face the industry. I really enjoyed the content, and some of the panel discussion surfaced many items around the challenges facing these groups. The industry stands to lose approximately $120 billion in patent-protected revenue over the next 2 years (which could mean the loss of 400,000 jobs within the top 12 pharma companies alone) - based on the panelists suggestions, there is not much to replace them in the market.

The underlying theme of the conference had been around creativity and innovation - trying new approaches, taking risks, becoming more creative in the alliances with smaller companies and those generating novel medicines, and engaging the payor community sooner to really target the problems which exist with today's therapies for a subset of patients.

Then, this news appeared:

GSK bets that hungry spinouts can upstage fat pharma (FierceBiotech, October 5, 2010)

"Big pharma is looking at productivity," Clive Dix, who helms the startup dubbed Convergence, tells the Financial Times. "It sees smaller companies as more fleet of foot. We are more focused and will be very hungry because the only thing we think about is these drugs."

For those who reside in the Northeast area of the USA, it was estimated that approximately 80,000 people lost their jobs due to mergers, downsizing, etc. A move like this one from major pharma companies suggest that the internal staff, processes and silo challenges inhibit the ability to move drug development quickly, reach and make decisions more expeditiously, and validate the money being spent is better served with smaller teams and fewer layers for approvals. Through partnerships with biotech companies, where the smaller entity is able to maintain the development of the product, this same sort of movement is possible. At the conference, it was noted that many of the alliances were structured to allow the autonomy of the smaller entity to continue on its path and fund their efforts. For those employed by larger entities, this movement is sending a clear message for sure.

This had me also thinking about the service delivery of our industry. Why are companies still leaning on the full service Contract Research Organization (CRO) structures and outsourcing in the traditional methods given this new sense of urgency around drug development? Many years ago, the CRO industry was born and grew around "mirroring" the larger pharma companies for which they served, and thus grew in their likeness. As indicated by the poor productivity referenced in the GSK example and the many years of very low New Chemical Entity output by the top companies, the full service CRO model provides the same layers and challenges within their models that challenge the larger pharma institutions. And many smaller companies find it challenging to stay a priority within these organizations when they are supporting tens and hundreds of larger pharma company trials.

Why is it that people today do not carry their creativity and innovation to their outsourcing strategy and their vendors? It seems almost self-defeating by creating and operating a small, virtual drug development organization who is nimble, quick and cost effective, only to hand the entire program back to a model which has shown by industry to be unproductive and costly? The extent of change orders and layers of overhead/management create difficulty to become intimate partners, and maximize the investments made by venture capitalists and others to provide an end product of high quality, delivered on time and within budget.

There are models being promoted, explored and created to foster the benefits of virtual service delivery using Functional Service Providers (FSPs). In these models and companies, you will find highly experienced artisans who focus on their particular niche, and are generally selected based upon their contribution to the team and study, not selected because they are employed by a company. FSPs assist the pharma industry with more cost effective drug development programs by companies who exhibit the same sense of urgency with their business practices as the forward thinking entities who employ them.

The move by GSK should cause concern for anyone operating in these larger models, especially those who support the services of these therapeutic teams. It will be challenging to compete against smaller teams built on years of experience and commitment to clients' deliverables.

Moving away from the perceived "safe" choice is challenging - many times, you are forced to change (which many claim is for the better). I cite my own personal experience when flying for business - our company was strained financially and was asked to drive the 8 hours to our office for meetings. Flights on a known commercial airline from Philadelphia were $900-1,000, even with a few months advance purchase. Then I noticed this airline - Southwest - which offered low fares, had clean planes, seemed to be full of energy; however, my perception was that they were for younger people and vacationing families - they had no first class (and I had all of these points and preferred statuses) - all of the "important reasons". Tired of driving and seeing them move into Philadelphia, the cost point was low enough that I was granted the purchase of a ticket on that airline. My first experience was Wow! - we boarded the plane at 6:05 am for a 6:20 departure. The stewardess came on board and, since we had everyone seated, asked if we would mind leaving early. WHAT? Leave early? We arrived 20 minutes ahead of schedule. I certainly have more "success" stories being a passenger on Southwest Airlines - they are now my first choice whenever I fly.

I was forced into this position, and it turned out immensely successful for me (obviously Southwest has done well despite the challenges facing the airline industry and those of their competition). Based on the tremendous lost amount of existing revenues and the lack of replacement compounds for larger pharma, and the limited financial support being provided to industry at present, the pharma industry is being forced to find alternative ways to accomplish their objectives. Being more creative and leveraging the services and technologies of Functional Service Providers, and groups who form their business models around FSPs, should be considered as one solution to provide the creative, innovative support required by industry's forward-thinkers.

Model-based drug development

In the 1990's and 2000's, there was an interesting change in role for IT professionals.  Once seen as the people who received help desk calls to support forgotten passwords and internet hook-ups, the implementation of an IT strategy elevated their positions to now include corporate strategy and assistance in driving overall efficiency in their companies. Pharmacometricians are on the verge of forging a new role with drug and device companies in much the same fashion.

New to the Harte Group suite of support companies is a modeling and simulation company called Cognigen Corporation.  I am impressed with the art of this science - the creation and use of quantifiable data for assessing the likelihood of success for a drug or device.  This science helps to eliminate much of the bias and emotion involved with decision-making (go/no go decisions).  It can also provide a wealth of support for ongoing studies (such as dose justification, effectiveness  on targets, appropriate sample size, etc.) and in post-approval (brand protection for proper assessment of investigator-initiated studies, design of additional studies to support safety and efficacy claims).  

This week, is was also comforting to learn that the FDA has implemented this science as part of their drug reviews and evaluations (www.bio-itworld.com/pb/2009/06/11/fda-pharmacometrics-gobburu.html).  While the science itself is not novel, it is gaining in popularity for its ability to help design earlier stage trials (phase I/II studies) with more impact.  For many drug and device companies looking to maximize their R&D spend, the use of pharmacometrics should be an integral part of the strategy.

I also find an ability for this science to be leveraged by venture capitalists.  This group is somewhat naive to the drug development space, but they certainly understand the return on investment when their drug partner receives an agency approval.  Many VCs have been resistant to invest in the biotechnology space because of the amount of investments required to get a drug to the point of in-license/out-license opportunity - in some cases, multi-millions.  The use of pharmacometrics by venture companies would allow for clinical studies to be properly designed, thereby providing support for the time and cost associated with activity required.  Appropriate milestones can also be identified for making go/no go decisions, and providing quantifiable evidence for future investment.  Along with thought leaders in the industry who interpret the clinical data, this is the closest means of monitoring the likelihood of success for a drug or device that can provide comfort for investors.

Every building needs a blueprint, and the use of pharmacometrics provides and supports the "blueprint" for drug and device development activity.  I am proud to be associated with the Cognigen Corporation, a group which has been providing these services for 15+ years and have received very positive feedback from many FDA reviewers alike.  In my due diligence, reports from the agency (FDA) suggest that review of Cognigen's material provides a high degree of comfort as the data is always well-defined, reports are always well-written, and the presentation of the materials are always "first class".  One reviewer suggested that "Cognigen Corporation has raised the bar in terms of how data should be assembled and submitted".

Harte Group - welcome

This website and forum have been created for sharing ideas and thoughts about challenges and solutions for the clinical drug development process.  More and more, sponsor companies of all kinds are finding comfort in the hands of functional service providers, or subcontractors.  The goal of the Harte Group is harness these companies and manage their activity to deliver a high quality, cost-effective and timely solution to the current paradigm of full service offerings.

I welcome your thoughts to this changing model and delivery solution for our industry, as well as exposing you to some of the best and brightest people in the industry.

Welcome to the Harte Group Blog!

Greetings! My name is Michael Harte, President & Founder of the Harte Group. You can click the links found at the top right or footer of this blog to go back to the main website. I am very eager to get this blog started, so please feel free to sign up!