QuickNote: Off Label Promotion Ruled OK by US District Court

In a ruling with huge potential impact on MA as well as commercial functions, the Court of Appeals for the Second Circuit in Manhattan has overturned a conviction of a salesperson who was promoting the off-label use of a product! This 2-1 ruling goes against years of court rulings stating that pharma does not have the right to promote off-label.  In fact,  in the past month GSK has been fined $3 billion for off-label promotion and J&J fined $181 million for off label promotion.

Clearly, new legal ground is being broken here.  BUT, if urge caution.  This is one ruling that contradicts years of previous rulings.  It may serve as grounds for kicking this up to the Supreme Court, but until clear legal direction is given I would not be changing any policies.

Take a look at the article here and the actual ruling here.

Topic 19 – EU Considering Major Change in P4 Trials

A new position paper has been floated by the European Commission Health and Consumer Directorate-General that may have HUGE impacts on the way P4 trails are conducted in the EU (and the rest of the world).  My take on it is below:

Stemming from the new EU regulations around pharmacovigilance, the EU is also considering the role of post-marketing efficacy studies (PAES).  In a position paper seeking feedback, found here, the EU lays out its perspective that the new PV legislation also refers to the possibility of requiring the market authorization holder to develop PAES to complement the efficacy data used to grant marketing authority.  That power is granted where “concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed.”

Regulatory Purpose

The position paper goes on to lay out the regulatory purpose of PAES and suggest that after the results of a required PAES were provided to the regulatory agencies, they would be free revisit the authorization decision and determine if “…the marketing authorization should be maintained as granted, varied or even withdrawn on the basis of the new data resulting from the study.”

While regulatory agencies have always been free to revisit their decisions, this approach seems to imply that they are obligated to reconsider their decision after the required PAES.  This makes thoroughly changes the role of the non-PV focused P4 trial from today’s approach to a much more high-stake trial.  Under this approach, these types of P4 trials would have much higher risk and would likely need to be treated much more like we treat P3 studies.  This means a likely significant increase in cost for these trials.

Efficacy vs. Effectiveness

The next section of the position paper focuses on the question of efficacy vs. effectiveness.  The paper comes down clearly on the side of efficacy.  Again, this could be a major change for P4 trials, many of which are focused on developing real-world effectiveness data to provide support for reimbursement decision makers.  This change may also force a significant revisiting of the P4 approach followed today.  Additional P4 trials may be needed if the mandated trials focus on efficacy and cannot be tasked with also considering effectiveness.  This will have a significant impact on time and budget as well.

Situations Where PAES May Be Required

The paper then proposes a set of 7 situations where PAES may be required.  They are:

Situation Where PAES May Be Required	Comment
1.   Studies aimed at determining clinical outcome following initial assessment based on surrogate endpoints	This type seems very logical.  If surrogate end points were used to get authorization, then a study may be required investigating the underlying endpoint sought.  But, this may significantly add to the cost of using surrogate endpoints for approval, since surrogates are sometimes used because of the time (and cost) of gathering data on the underlying endpoints.
2.   Studies on combinations with other medicinal products	Acknowledging that testing for authorization can only cover a limited range of combinations, P4 trials may be required to test additional combinations.
3.   Studies in sub-populations	Given the limitations on the number of sub-populations, additional sub-populations may be required to be tested.
4.   Studies in the context of the European standard of care	If the trial uses subjects primarily from outside of the EU, the EU may request additional information from patients treated within the EU.  This would negate any cost savings a company might hope to garner by working in other markets.
5.   Studies linked to a change in the understanding of the standard of care for the disease and/or the pharmacology of the medicinal product	This is a scary one.  It proposes that if the standard of care for a disease had changed, the authorization holder may be required to develop new efficacy data addressing the new standard of care.  This could result in a never-ending need for new efficacy trials – a major change in way we think of authorized products.
6.   Studies aimed at determining the long-term efficacy of a medicinal product	This is one of the “traditional” reasons for P4 is long-term analysis.  Difference is focus on efficacy instead of effectiveness.
7.   Studies in everyday medical practice	The proposals suggests that these would be required when “…there is clear evidence that the benefits of the medicinal product underdiscussion as shown by randomised controlled clinical trials might be significantly affected by the real-life conditions of use.”  This seems to open the door for any misgivings or concerns by the regulatory authorities to result in the requirements for a trial – and when they get results they will be obliged to revisit the approval.

Final Thoughts

While this is still in proposal stage, the direction is clear.  PAES is going to become a new tool for regulators who have efficacy concerns about both new approved and legacy products to address their concerns.  It is likely to have a significant impact on the cost, risk and structure of Medical Affairs if it comes into effect.

I urge you if you have comments to follow the process found in the document to express them.  I will be doing so.

What are your thoughts?  Am I overreacting? Please leave a comment.

h/t PharmExecBlog

Topic 18 – Site Payments in Phase 4 Clinical Trials

(Full Disclosure – I was introduced to this issue by my client who has a interest in the solution to the problem but regardless I believe this to be a real problem. )

As P4 clinical trials grow larger and more complex, the challenge of site payment computation and accrual grows as an issue.

As more and more sites become sophisticated partners in clinical trials they are demanding customized contracts with payment terms associated with their work and cash flow needs.  It is hard to blame them when pharma and CROs has been so bad about paying, many times paying sites over 90 days after the site incurs the cost and paying inaccurately.

Payments are a source of friction with PIs and thus KOLs.

CenterWatch has identified late payments as the #1 site concern about pharma for the last three years. For a P4 study, Principle Investigators (PIs) are often key opinion leaders (KOLs), since many of KOLs have access to the type of patients needed for the trial.  Developing a strong scientific dialog with KOLs is a fundamental role of MA.  Yet, at the same time we are working so hard to establish a positive working environment to collaborate with KOLs, we are also degrading that relationship due to late or inaccurate study payments.

It is not at all unusual for an MSL to receive complaints about late payments on trials, even though the company has outsourced the trial to a CRO for payments.  The PIs will hold the company responsible despite the CRO’s involvement.

Payments are a source of regulatory risk.

Since payments are generally computed manually even by most CROs, many mistakes are made.  Thus at the end of each study there is a process called “End of Trial Reconciliation” when the actual amounts owed are computed against the final data collected.  Any missing money (and there is often hundreds of thousands in overdue money) is paid at this point.

BUT, the regulatory risk is not in delayed payment.  The regulatory risk is what happens if we find we have paid too much.  This happens often in clinical trials because due patients drop out but due to computational errors the site still receives payments for that patient.  If that occurs we have overpaid the site and the PI (which we discussed are also KOLs).  But this computation error may be from years before.

Now the quandary is – do we demand repayment from the site for our error.  Technically, the site should refund the overpayment.  But, I would ask your operations group if you have ever asked for that money back.  My practical experience is that the overpayments are rarely if ever collected back.  If they are not collected back, we have essentially paid more for the trial than fair market value and thus we have a potential compliance issues.

While this issue has not been one I have seen enforced to date, given the growing scrutiny on all payments to physicians with the Sunshine Act, I think it would be wise to ensure that this risk is avoided.

Payment computation is a hidden cost. 

With these more sophisticated contracts comes the need to administer them and compute payments.  Sites don’t send an invoice.  So, determining the amount to pay is left up completely to the pharma company.  Performing that computation can be complex and time consuming.

Since many pharma companies outsource their P4 trials, what they are doing is paying the CRO to perform this computation for them.  In some larger P4 trials, hundreds of thousands of dollars in fees are spent for the CRO to compute and issue payments.

New solutions are available.

The good news is that a new type of software is being developed to automate the payment process and avoid the need to do any manual calculations.  If you are interested check them out .  My client is www.clinverse.com.  Also their competitor is www.greenphire.com.

What has been your experience with P4 site payments?  Leave your thoughts in the comments.

QuickNote: The Sunshine Act is Here to Stay!

Given the results of the presidential election, the remaining hopes I have heard expressed that the Sunshine Act would not be implemented should have evaporated.

We have already discussed here some immediate work MA needs to do to start prepping the ground for the data.  While it is looking likely that implementation may be delayed, MA leaders should be planning for this in their 2013 budgets.

Any other impacts of the election that MA leaders should consider?  Leave your thoughts in the comments.

Topic 17 – New MA Organization – MedComm/SciComm

A reader and I discussed her dilemma the other day.  She was being tapped to create a new MA function for a small biotech that was bringing its first product to market.  She had fairly broad latitude but was not sure where to begin.  Some of the points of our discussion are captured below.

We have already discussed preparing an MA team for launch here, the effective way to manage MSL groups here  and the best way to develop a MedInfo function here, I thought I would focus on the Medical Communications or Scientific Communication group with this post.  A note about function names.  I very much prefer the term Scientific Communication because it more correctly reflects the role of the function which is to provide scientific data to the market place some of which is purely medical but some of which may be of a health economic nature that are not purely medical.

SciComm is a critical function for MA but developing one from scratch is as much a challenge in internal politics as a challenge in terms of operations.  At a small company, before there is a SciComm group the company is already publishing.  So, developing a group can be sensitive and many toes can be treaded upon if one is not careful.  The best approach is to co-opt the staff that have been driving the publication efforts in designing (and maybe leading) the new SciComm function.  But, it is critical that everyone involved realize that publications take on a broader role in SciComm than they did in CD.

In CD the role of publication was primarily focused on the results of clinical trials.  That continues to be a responsibility of SciComm but its role of sharing scientific data expands to identifying the scientific questions that the marketplace needs answered, some of which will be answered through literature analysis or through non-clinical studies.

Given that CD is typically handling the publications in advance of the SciComm function, the temptation may be to put developing the group on the back burner until other MA functions have been more fully developed.  This would be a mistake.  SciComm needs to be analyzing the scientific needs of the HCP community and ensuring that the required scientific information is available concurrently with launch.  Any delays can result in a vacuum of information and who knows what will fill that vacuum (or which competitors will try to fill that vacuum).  So, at least 18 months prior to the launch the SciComm group should be launched, right along side the MSL function.

What has been your experience with SciComm groups at launch?  Leave a comment.

Topic16: Greater Clinical Trial Transparency and Medical Affairs Rapid Response

GSK announced this week that it would open up its clinical trial data sets to researches who receive approval from a GSK review board.  Next year, the EMA intends to open up access to all new clinical data files that are part of a product registration filing.

I believe this is a trend that will not stop – the increasing openness of biopharma with its clinical trial data.  What does this mean for medical affairs?  I have some initial thoughts below but I would be curious to hear your perspective.

As this data becomes more open, other scientists, some perhaps not fully qualified to understand the data set, are going to review it and draw conclusions.  Since our culture has incentives for publicity in academia, expect that at least some of the scientists are going to spin the data into the scariest sounding headline they can.

The result is, I predict, a sharp rise in news stories highlighting safety risks of products, often blown out of proportion.  Nevertheless, it will ultimately fall to MA to deal with this misinformation on the scientific side.   While this can happen today, it is still fairly rare.  I believe it is going to be common place.

In order to be ahead of this, MA leaders are going to need to set up a Rapid Scientific Response capability (if they don’t already have one):

• Identify Potential Areas Requiring Responses  –  First step is determining what potential areas require rapid scientific responses.  Start with a brainstorming exercise and prioritize to get to the top 5 to 10 topics.


• Determine Leader of Response – For each topic area, identify who from the MA or other functions team should take the lead on coordinating the rapid scientific response


• Identify Internal Experts and Voices – Search through the organization and determine who else has the scientific expertise and other skill sets needed to support the rapid scientific response – PR and Legal should be a part of each team


• Develop Rapid Response Plan – Create a plan for assessing the situation, determining the outline of the response, assigning elements to team members, pulling it together, getting it reviewed and getting the message out  

The entire goal of develop the Rapid Scientific Response capability is to be able to move quickly when the event occurs and produce an accurate and complete response in as little time as possible.  Without this advanced planning, when issues hit no one is clear who should be taking the lead and how.

Do you have a plan for Rapid Scientific Response?  What other impacts do you think the increasing openness of clinical trial data will bring to MA?  Leave your thoughts in the comments section.

Topic15: OLIS and Journal Clubs and Journal Articles

I was talking with a friend and client about internal journal clubs in particular and discussing journal articles with HCPs in general. This discussion may be germane to a number of you because it really stems from what I think of as “Overactive Legal Imagination Syndrome.”

OLIS is the reality many of my clients face when their legal group begins to tie itself in knots over the practical implications of the fact that MA must talk about the science involved with its products, and some of that science may ultimately be compelling enough that the HCP decides that our product is something that they should use.  OLIS drives them to wonder “How can we not be promotional if the results of our permissible scientific exchange is that the HCP decides to use our products?”

See our thoughts below:

1)      Can we allow Internal Journal Clubs?

• We already agree that field staff can have permissible scientific exchanges with physicians


• In order to have scientific exchanges they need to know the latest science which is represented by what is being published in peer reviewed journals


• Although our team is good, no one member of the field force has all the knowledge necessary to understand the huge range of potential scientific articles or the time to cover the huge range of journals


• As a group, however, they do posses both the knowledge and the time


• Therefore, they should be allowed to review the new scientific information as a group and share with the members the information they need

2)      What if the conclusions reached in the internal discussions of the articles are biased?

• So what? – we are not going out to the HCPs to present our conclusions but to have a scientific dialog – to listen and answer scientific questions


• Any perspective we have is already perceived to be biased – we work for a major pharmaceutical company and everyone knows it


• The issue is not bias – which is not against the law – the issue is promotion

3)      What if our perspective is deemed to be promotional?

• There is absolutely nothing new about a concern that our scientific dialogs run the risk of being promotional


• BUT, we already have standards and training in place to ensure our staff does not promote during scientific exchange – regardless of whether that exchange is about a new article in a journal or an existing safety issue, etc. etc.

4)      What if the conclusions of the author of the journal article are promotional in and of themselves?

• First, we need to agree that facts, even facts that are favorable to our products, are neither promotional nor non-promotional – facts are facts


• Conclusions drawn from the facts can be promotional


• So if the study finds that patients using our drug have better results than patients using a competitive drug, that fact is NOT promotional UNLESS our field staff says something like:

i.     “I don’t see  how anyone can read this and not put all their patients on our drug”

ii.     “Clearly our drug is the more effective and it wouldn’t be ethical to put your patients on any other treatment”

• If the author of the article draws their own conclusion “…and in the opinion of the authors you would be a fool to treat with anything but X.” then we are back to the points in number 3 above, meaning our team needs to know a promotional statement when it sees it and avoid repeating it


• In this scenario, the internal journal club is actually of value to the company because it allows the group to identify this potentially promotional author conclusions and agree on strategies to engage in this topic without endorsing the author’s conclusions


• Bottom line – these “promotional conclusions” drawn by independent 3^rd parties and published in peer reviewed journals are out in the public sphere and keeping our field team from understanding the article and agreeing on an approach to addressing it without a promotional bias will not stop HCPs from asking them about it and forcing some kind of reply

What has been your experience with OLIS?  What about internal journal clubs?  Leave a comment.