Pharma Reform

Corporate integrity should start at the top of the organization and every employee must do their share to make it a reality but pharmaceutical company physicians and scientists are the best hopes for reestablishing pharmaceutical industry trust… if they can survive in their organizations.

Integrity and objective science were once the hallmark of pharmaceutical research.   Valid testing methodologies, rigorous analysis and interpretation of data, and accurate complete disclosure of findings and understandings provide the medical community with a sound basis for making informed clinical decisions.  Too many case studies over the past several decades, however, have raised serious questions about the integrity and objectivity of pharmaceutical research.

Not to make excuses but, physicians and scientists at pharmaceutical companies are subjected to intense organizational pressures that can cajole them into compromising their objectivity and scientific integrity.  These pressures come in subtle and sometimes not so subtle forms.  Emotional attachment, satisfaction of personal ambitions, peer pressure, and management can all influence decision making and can provide a rationale for questionable actions taken.

Emotional attachment results from years and sometimes careers worth of product development, creating an instinctive need to nurture and protect “their babies”.   Wanting to maintain a positive outlook, securing incentive compensation, enhancing professional stature, and wanting to be a part of the team can all drive the behavior of individuals and groups to do things they might not otherwise consider.

Perhaps the single biggest challenge for industry physicians and scientists trying to maintain scientific integrity is dealing with the implicit and explicit demands and expectations of management.

Some of the types of scientific integrity issues we are talking about include:

• Designing studies around problems without disclosing the problem
• Data manipulation
• Covering up, hiding, or minimizing relevant negative data
• Disproportionately highlighting efficacy benefits to mitigate safety issues
• Not challenging or correcting company statements (or marketing) when they know they are scientifically not valid, incomplete, or misleading

None of these happens in a vacuum as it would be rare that they could be accomplished by a single individual without the knowledge of others.  At the same time, an individual physician or scientist puts their career at risk when they challenge organizational thinking and management prompted or endorsed indiscretions.

That being said, pharmaceutical industry physicians and scientists are often the only ones who have the corporate platform and organizational position power to guide management regarding what can be supported scientifically or what can or can not be claimed clinically.   They are in the best position to insist on integrity in drug development as well as in how the company promotes its products. They are in the best position to clarify and correct misleading corporate commentary, statements, or implications.

When integrity and objectivity of the science around a product are ensured, when scientists hold their management accountable for accurate and complete disclosures, and when they don’t let marketing and sales make misleading or false claims, then pharmaceutical industry physicians and scientists will provide the basis for restoring confidence and credibility in the work they are doing.  An organization that embraces integrity will value these physicians and scientists and reward them for keeping the company honest.  Unfortunately, companies that do not embrace integrity will probably find a reason fire these these physicians and scientists, if they don’t decide to quit first.

mike@pharmareform.com

A change of heart at Stanford Medical School allowed it to accept $3 million from Pfizer for CME after having publicly denounced the inappropriate financial influence of industry on CME. The draconian ACCME decision regarding AHA (American Heart Association) meeting restrictions on industry presentations could have had serious financial implications for AHA if they had not defended their peer review screening process and the desire to have industry scientists on their programs.   Although there was considerable support for the research information sharing value of industry participation,  I also suspect a considerable amount of industry financial support could have been at risk including major sponsorship commitments, exhibit space sales, and other marketing opportunity fees.   And now the state of Massachusetts is having second thoughts about restrictions they have placed on pharmaceutical sales representative activities (e.g., pens, sticky pads, and free lunches) because of the negative financial impact the restrictions are having on local businesses.

Are we getting to a point where the level of ethical and conflict of interest concerns about pharmaceutical industry influence will be moderated more by the level of financial impact than the convictions of those imposing the restrictions?

Here is one way to keep people honest about their ethical and conflict of interest considerations when restricting pharmaceutical industry activities.

It is the right of these groups and organizations to regulate and even ban pharmaceutical industry activities.  But,  if industry influence on prescribing and concerns for conflict of interest are seen to be detrimental to patients and are the basis for these decisions to preclude the industry from participation, then the restrictions and the need to avoid these influences should apply in principle to all members of that group or organization as well.   There are now a sufficient number of cases which demonstrate physicians and scientists are not immune to breaches of integrity and have been equally responsible for creating these concerns for biasing information about prescription drugs and participating in the creation of conflicts of interest.  Therefore the restrictions should apply to both sides of the activities of concern.   Here are some examples of how they should apply to Massachusetts or for any other organization with pharmaceutical industry restrictions:

• No physicians in the state of Massachusetts (faculty member of Stanford or AHA member, for example) should be allowed to accept any fees from industry, even for legitimate advisory, consulting services, or Board of Directors participation.  These individuals are selected for their expertise and they could be influenced by these payments (more so than a free lunch or pen).  More importantly, these individuals, because of their expertise and influence, have the capacity to influence (pass along biased information) far more physicians in private conversations and even in non-industry sponsored programs.
• Massachusetts licensed physicians and other healthcare providers (or from other restricting groups) should not be allowed to participate in any industry sponsored meetings or conferences.  This includes any national society meetings or conferences or scientific meetings sponsored by industry.  A pharmaceutical company merely being seen as a sponsor could favorably influence a physician about their views of the company and their products. Not to mention the exhibit area influences they would be subjected to.
• No medical meetings or events sponsored by the pharmaceutical industry should be allowed to be held in Massachusetts as this would be encouraging the very behavior (inappropriately influencing physician prescribing) and activities they are trying to curtail with their restrictions.
• Clinical studies are powerful ways to influence prescribing, especially for new products.  Therefore, clinical studies should not be done in Massachusetts (or other restricting institutions).  If they are done they should be done for no fees with only nominal, non-compensation related administrative expenses being reimbursed.
• Research grants and funding have the potential to favorably influence prescribing practice, especially if the data are published under the reputable name of the institution.  Therefore, no industry sponsored research should be conducted at or in institutions other than drug, life science, or biotech companies within Massachusetts.  No industry sponsored research should be allowed at any state facilities or their affiliates.

While these may have significant negative financial implications for individuals, businesses, and organizations, this mutual implementation of restrictions would preserve the integrity of decisions made to avoid conflicts of interest and limit the perks and financial influence of the pharmaceutical industry on prescribing practices.  In fact, these restrictions would have a far greater impact on assuring the elimination of industry influence than taking away pens, pads, and free lunches.

I suspect the negative financial impact will probably be far too great to allow ethics and decision making integrity to prevail in most situations .  As long as it makes financial sense for Massachusetts or other organizations,   the restrictions and expectations for compliance will be one way (only the industry must be controlled and comply) and will not really be driven by the ethical and integrity convictions of those imposing the restrictions.

mike@pharmareform.com

The healthcare market is becoming increasingly demanding of the pharmaceutical industry to deliver products that are innovative and that can demonstrate clinically meaningful differentiation from currently available treatment options (including generic drug alternatives) .  This hurdle will become even more challenging as more mass market blockbuster products come off patent over the next five or so years.

The sources for these innovative products have historically been Pharma discovery research, start-up biotechnology companies, and university laboratories.  With a disappointing track record over the past decade or more, pharmaceutical companies have been narrowing their focus and downsizing their research efforts in favor of in-licensing technologies for development.  Looking for reduced risk and higher return on investment opportunities Pharma targets late stage technologies with proof of concept and a high probability of scientific and technical success.  Unfortunately, virtually every pharmaceutical company is now evaluating the same finite supply of technologies to find the few that fit the innovative, late stage, high probability of success profile.

Although one might expect a regular replenishing of the supply, this  should not be taken for granted.  While universities are fertile grounds for therapeutic concepts, targets, and interesting compounds,  few can afford or have the expertise to take potential drug candidates to proof of concept in a regulatory acceptable fashion that will mitigate the risk sufficient to warrant Pharma investment.   As a result, the diminishing supply of investment- worthy late stage programs is about to be exacerbated by the lack of adequate early stage discovery research funding.

At the same time, Biotech companies that can transform these promising technologies into viable development candidates have been starved for cash for the past two years making it nearly impossible to sufficiently fund new projects much less keep current programs adequately funded.  What this means is that the university/biotech pipeline of innovative new products that Pharma is counting on may soon become depleted if it isn’t already.

The obvious solution is for Pharma to accept more risk, invest much earlier, and collaborate.  Given the challenges of drug discovery research and the time required to get programs to proof of concept, Pharma may not have much time before the lack of discovery stage funding creates a gap in the flow of innovative pipeline products far greater than has ever been imagined.

mike@pharmareform.com

Pharmaceutical and biotech company marketers have always appreciated the impact they could have with pharmacoeconomic data to support the advertising and promotion of their products.  Unfortunately, it was rarely a prerequisite for commercial success and more often than not, done after product launch using retrospective database analysis and speculative modeling.  In the evolving new healthcare market that will change.  In an increasingly managed and cost conscious market, even innovative products with meaningful clinical differentiations from other therapeutic alternatives will be expected to substantiate the value of that differentiation.  So how do you deliver on those expectations?  You start early in development.

Pipeline project evaluation:

• What are the target product profile value drivers? Specifically, what are the points of differentiation;  the reasons why this product will be better than what is currently available or that might be available at the time of product launch?
• What are the plans for proving that these points of differentiation are clinically real and meaningful?
• Will it be possible to include these points of differentiation in regulatory labeling (package insert) so they can be used in marketing programs?
• Can marketing ascribe a quantitative value (cost benefit) to these points of differentiation?  What are they worth to the patient, to healthcare providers, and to the payer?
• Have you modeled the potential value of the differentiation and the minimum comparative value that is going to be meaningful to payers?  At what point, does the differentiation no longer have meaningful value?

Clinical development:

• Are trials designed to deliver data to prove the points of differentiation?
• Are the trials designed to capture the quantitative value of the differentiation?  Have credible, valid pharmacoeconomic metrics been used?
• Have you eliminated bias from the quantitative design elements?
• Have you built in conservative pricing assumptions and options?  Are they sufficient to allow for valid sensitivity analysis?
• Will the value assessment be reproducible in the real world?

This approach relies heavily on the marketing team understanding the value expectations of the market, the competitive value propositions, and the impact of pricing on the value proposition model.

The research teams must look at not only trial designs from a regulatory perspective but also must be accountable for delivering the definitive proof of differentiation and the data to support the quantitative comparative value (pharmacoeconomics).

Many pharmaceutical marketers do a series of market research studies and then typically set a price based on competition and “what the market will bear”. They then try to justify the value when they go to market.  Now, marketers will need to appreciate, very early on, the relationship between the price they set and the value they can prove based on that pricing and the available clinical and pharmacoeconomic data.   Comparative value assessments by payers will be data driven and will not be influenced by marketing hype.

I’m certain that some who have read this post will think that this process is idealistic, impractical, and some might even argue it is not necessary.  That is might be true until they realize their competitors who are developing comparative value data are creating a substantial competitive advantage and increasing the probability for more ready access to drug formularies at premium prices.

mike@pharmareform.com

Most Big Pharma development programs focus on regulatory requirements for FDA approval.  Makes sense.  There is no commercial value in a product that can’t get approved.  Healthcare reform and the evolving new market, however, are going to impose another level of expectations that go well beyond FDA product approval.

Big Pharma research teams often develop elaborate target product profiles that provide the reasons for developing drugs in the first place.  New mechanisms, less of this or more of that, better dosing schedule or something that makes the product worth developing.  These profiles often provide the theoretical rationale for why the product is better than what is out in the market.  These points are also highlighted every time a budget is reviewed to support continued investment in the product.  Unfortunately, few development plans reflect “proving” these points of differentiation.  Being able to demonstrate “better” for your product compared to other therapeutic options, including generic drug alternatives is rarely part of a regulatory path to approval.  In fact, being “as good as” or “not worse than” is the statistical goal of most programs.

So holding research teams accountable to deliver the “differentiation” proof and data would be one place to start, especially in the face of market expectations for “comparative effectiveness” studies.  But here is the real kicker.  Even if they can demonstrate some clinically meaningful superiority to an available alternative treatment that doesn’t ensure market acceptance with widespread adoption or that the product will become the “treatment of choice.”   I’m not talking about product launch failures or poor commercial execution issues here.

Once the company has demonstrated (solid clinical data) a clinically meaningful difference it will have to have data to show that the difference is worth paying for.  This will be especially challenging when the alternatives are less expensive generic drugs.  I can hear the formulary verdict already.  “We have determined that your product is clinically better than the treatment options available to us but the price difference doesn’t’ justify including your product on our formulary.”  What the market will really be asking for is “comparative value” data.

We’ll discuss what companies should be doing to deal with this in the next post.

mike@pharmareform.com

Biotech has proven to be a viable source for innovative new drug products.  The healthcare market’s increasing demand for innovation and the need to fill gaps in Big Pharma’s research pipelines in the face of blockbuster product patent expirations have driven Big Pharma to get a lot more aggressive in seeking innovation outside their own research teams than they have been for decades.

There are five critical success factors that could help the relationship between Big Pharma and biotechs remain a productive source of innovative new products for the healthcare market:

1. Pharma must respect the scientific expertise of the small biotech companies and  resist the temptation to impose its bureaucracy and corporate expectations on the research teams of the smaller biotech companies
2. As much pressure as there is to get products and technologies to market, it is important to make sure the science of these biotech innovations is allowed to be fully vetted before they are advanced to clinical trials.  Pushing technologies into and through development only to be disappointed by the clinical results in Phase 3 trials  may prematurely, inappropriately, and misleadingly dismiss perfectly good products that are not given a valid scientific chance to succeed.  Small modifications or adjustments in chemistry or better defined or better chosen clinical endpoints might lead to success where failure lurks.
3. While there is a robust diversity of innovation being worked on at universities and in small biotech companies, the number of projects that will result in commercially viable innovative products is still finite at any point in time. And because innovation often starts in the university lab, Pharma should be looking for ways to finance and collaborate much earlier with basic science programs at universities to make certain the flow of innovation continues.
4. Technologies and innovative products directed at a particular therapeutic target or disease are frequently dispersed across multiple companies, across different universities, and even across multiple departments within a university.  Pharma should develop programs to help facilitate collaboration amongst these disparate programs and projects to exploit the expertise and increase the probability of finding the best solutions for treating and possibly curing diseases.
5. Universities and small biotech companies must better understand and appreciate the financial risks Big Pharma is taking in providing support at early stages of development and manage their financial expectations accordingly.

mike@pharmareform.com

We live in the reality of a world where skillful chemistry and quick structural modifications can develop new but similar drugs.  Some of these new products may provide benefits such as avoiding  side effects or reduced dosing schedules.  But for many, these products create one of the biggest challenges facing pharmaceutical marketing today.  Being able to develop and establish meaningful product differentiation.  In most cases, the lack of sufficient clinical data to support the desired claims makes this near impossible  within the confines of regulatory constraints.  Without clear, science supported product differentiation; marketers are left to creativity and expensive high visibility market presence to create a competitive advantage.  Sometimes this involves stretching the data and claims as far as you can get away with from a regulatory and legal perspective. Sometimes this means outspending your competition to make sure your product gets sufficient market exposure  to create demand.  Sometimes it means competing on price.

There are two solutions to this dilemma.  The first is for R & D to deliver truly innovative new products with the clinical data to substantiate the novelty and value. The second is spending more money doing clinical studies upfront on products that are suspected of having some element of differentiation. Design trials that can support the claims you want to make and make certain the studies and results have the scientific rigor to pass regulatory muster and are sufficiently compelling to make it easy for your marketing staff to communicate the differentiation without exaggeration.

I realize neither of these solutions helps those with difficult to differentiate products today.  Unfortunately, you are left with traditional tactics for trying to create that competitive advantage.  This situation does, however, point out the importance of experienced marketing input to R & D…early.  As the market expectations increase for differentiation (remember “comparative effectiveness”?), building a strong scientific foundation around the product claims you want to make will become essential for commercial success.  The days of clever marketing and sales to “push” products into the market are limited.   Spend the money upfront on more and better clinical studies and increase the credibility of your marketing and sales.

mike@pharmareform.com

The answer to sustainable growth in the pharmaceutical industry is a continuous flow of innovative new products the market is willing to buy at the prices that make it worth doing.  Back in the 1990’s and early 2000’s, when industry R & D seemed to be able to produce whatever products were needed, it was nearly impossible for struggling small biotech companies to even get an audience with Big Pharma R & D to discuss their innovative new technologies.  The “not invented here” mentality that kept potential new treatments from Pharma R & D I believe has now come back to haunt the industry. Given the 10-15 year development time for new products, the math would suggest the 1990’s would have been a good time for risk taking exploration of innovative new technologies and aggressive licensing.  While some might suggest biotechs wanted to much for their technologies, I would argue, most never got to that stage of discussion.

Unfortunately, we will never know how many truly innovative products met their premature death at biotech companies that could not find sufficient funding to continue development or who were unwilling to give away their companies to Venture Capitalists.  Yes, the industry figured this out to some extent recently, but too late. And even now the rigors of a Big Pharma due diligence reviews are painful and beyond the resource capabilities of most small companies.  How many technologies get written off because the company doesn’t know how to present the technology to Big Pharma or because they didn’t do the studies a Big Pharma would have?

Pharma business development and R & D need to look at technologies not with a “quick to market” mentality but how they might be able to exploit technologies, perhaps even beyond where the biotech has taken the research.  Biotechs need to also be realistic about financial expectations and the value added by Pharma R & D and commercialization capabilities.   Unfortunately, the 1990’s may have been a missed opportunity but I also fear a lot of valuable technologies and innovative product opportunities may have died during the financial crisis of 2008-2009, due to Big Pharma evaluation criteria and expectations.

mike@pharmareform.com

Drug information sharing in the past provided an important role for sales reps, Medical Science Liaisons, and even journal advertising.  Even back in the mid-1980’s I remember doing online research (think dumb terminal with phone couplers) for infectious disease experts in their offices.  For most, their only alternative to get this information was to sit with the Med School reference librarian and try to figure out how to get what the physician needed from the National Library of Medicine database.  Searching was actually a skill back then.  This was probably as cutting edge at the time as you could get for information retrieval and sharing.

With the advent of the internet, robust search engines, and the pervasive availability of electronic retrieval devices, calling on physicians to do literature searches became limited in value.  Now these experts can do their own searches from their own computers. What’s the point?

For the industry to add value through information sharing, it is going to take more than sending a sales rep or MSL to see a physician with basic company product information.  Most companies realize this and have moved to take advantage of the internet, e-learning, e-prescribing, and television. In time however, this will also get old, build skepticism, and diminish in value as marketers abuse these tools, trying to cleverly hype  their product advantages, and overcommercialize their products with bold intrusive branding.

So what’s the solution?  Better science.  FDA approved label claims for what you want to say about your product and strong definitive clinical data to support the claims.  Peer reviewed presentations and publications with full disclosure and fair balance of data to support the benefits and risks. If you want to claim superiority, do the studies, get the claims, or at the very least, have credible data from reproducible controlled trials.

Then use whatever electronic communications you chose to disseminate your data.   This is not to say you don’t need marketing or sales to promote your product.  Professional, data supported claims merely provide a more credible base for promotion.  No hype required. You could even have life science trained medical personnel who can discuss in detail, on a peer basis, the nuances of the data and what they mean. If these people can not stand in front of a medical conference and defend their presentations, comments, or the implications of the data being presented, they should not be presenting in a one-on-one setting either.  A very tough standard, perhaps.  But, a lot more credible than the industry has provided healthcare providers in the past.

mike@pharmareform.com

During the discovery process, Pharma researchers explore molecular systems searching for and testing biological pathways and targets they might be able to turn on or off in an effort to mitigate disease symptoms or to avoid side effects and adverse reactions.  Drug discovery is becoming increasingly challenging, especially to find those elusive innovative new products the market is demanding.  To find those truly unique compounds, Pharma will have to delve even deeper into the biology and pathophysiology of disease.  This is fertile ground for Pharma companies to exploit by developing complimentary diagnostics to go along with their new treatments.  Developing these diagnostics could become a significant competitive advantage, a market embraced marketing tool, and may eventually be a necessity for commercial success in the not too distant future.

Here are some of the reasons why and how a Pharma company might consider developing diagnostics to go along with their new treatments:

The healthcare provider need for better diagnostics:

1. To more definitively identify diseases and their underlying cause
2. Disease identification rather than indirect diagnosis from lab data interpretation
3. Rapid, easy, “bedside” or office practice testing rather than time consuming, remote laboratory testing
4. To identify high risk patients who should be considered for preventive treatment

The market needs for better diagnostics

1. Desire to know which patients are more likely to respond to which treatments.
2. Desire to know which patients are more likely to experience side effects or adverse reactions
3. Tests to determine whether or not a treatment is actually working (having the desired affect)
4. Better treatment specific diagnostics could lead to less wasteful prescribing and avoid costly hospitalizations related to adverse effects

Regulatory considerations

1. Treatment specific diagnostics may provide a quicker path to proof of concept
2. Treatment specific diagnostics may be able to better establish drug superiority to alternative therapeutic options
3. May provide  stronger, more definitive  clinical support for efficacy and safety

Pharma companies looking to take advantage of this opportunity will need to:

1. Increase their research expertise to include diagnostics development expertise
2. Build corporate expectation that new treatment discoveries will come with a need for diagnostics to support the product
3. Expand discovery research to include looking for diagnostic possibilities
4. Include diagnostic companies, research tools and services companies, and other general life science companies in their business development licensing and partnering plans.

Diagnostics development to compliment drug discovery may be one of the most important strategic decisions a pharma company can make to increase their R & D productivity and stay aligned with the evolving new healthcare market.

mike@pharmareform.com