Medical Affairs Focus

Thoughts on Global Medical Affairs

Topic 41: The Implications of Amarin. Is It “Good” for MA?

A number of my friends in MA leadership have been debating the implications of the Amarin case for MA overall. Spoiler alert – I think it will prove to be another avenue for MA to add value and I will share my rationale below.

In case you have not been reading up on this case, you can see my brief discussion and some links to other sources of information on this blog post. When discussing the Amarin case it is critical to understand the context – this case was decided by a federal district judge in Manhattan for the Southern District of New York – so obviously this ruling does not set national standards. However, the Southern District court is one of the most influential and active courts in the US and it has a history of leading the nation.

Assuming that this ruling becomes the precedent for either other cases in other districts or even national cases, the question is if/when pharmaceutical companies have the flexibility to promote off-label data (with all the fair/balanced caveats) – what are the implications for MA?

So let’s go on a trip to a speculative future in which the ability to share off-label data with HCPs on proactive basis becomes accepted in the US. In this future, I would fully expect that the FDA decides to put guardrails around this freedom. Their rationale will be simple – there is high risk to patients if HCPs make decisions based on off-label information which have not run the full risk/benefit analysis of a product with an approved NDA. What would these regulations look like? We can get a good view from FDA’s response to Amarin (which we covered in detail here) the summary of which is that this education would need to be fair and balanced and, among many other things:

  • Discussions should be conducted by persons with the appropriate background or training to accurately communicate scientific information

That would clearly call for a role similar to the MSL or field force role of today’s MA. But would that role need to be in MA, or more provocatively, would MA need to be a separate entity from commercial.

Those you that have been around the industry long enough remember when MA was sometimes a function of commercial, often called Scientific Sales. Driven by increasing FDA and EMA scrutiny primarily concerning off-label promotion and a desire to be seen as a voice of science instead of promotion, MA as an independent, non-promoting entity became the standard.

In our speculative future the US has loosened the off-label promotion rules, but the EMA has not and the need for an independent voice for science has not decreased so I do not foresee an effort to move MA back under commercial. Frankly that ship has already sailed since so many other functions that MA serves also benefit from it being independent from commercial.

So if MA is likely to remain independent would the MSL role remain in MA? I think that they would, not only due to inertia (although you can never over-estimate the power of inertia in pharma) but also because keeping the MSL role in MA would improve the case that the information presented was fair/balanced and not tainted by promotional messages.

Following my logic stream, MSLs would gain a new capability (ability to pro-actively share off-label data) while remaining in an MA function independent from commercial – so a net improvement to the value that MSLs and MA overall brings to the company. That can only be a good thing for MA leaders.

That was quite a bit of speculation – what is your opinion? Please click here to leave a comment.

Topic 40: BREAKING: Court Rules FDA Cannot Prevent Truthful Off-label Promotion

In a court case that may have huge implications for pharma, a federal district judge in Manhattan ruled that the FDA cannot prevent a company from conducting off-label promotion if the promotion is truthful and scientifically accurate.

This ruling stems from the Amarin case that we discussed HERE.  In that case, Amarin argued that the precedent set by the Caronia case (which we discussed HERE) allowed them to promote off-label if the information shared was truthful and not misleading.  The FDA argued that the Caronia ruling was specific to those circumstances only and did not apply to Amarin.  Judge Engelmayer wrote in today’s ruling that “…A fair reading of that decision refutes the F.D.A.’s view that the Second Circuit’s ruling was limited to the facts of Caronia’s particular case.”

While this only currently applies to the circuit in question, it is a clear precedent that will need to be addressed if the FDA intends to retain its current regulatory approach to off-label promotion.  The FDA has not stated whether it intends to appeal but it did not appeal the Caronia ruling, a decision some pundits felt was made to avoid having a broader precedent set for allowing truthful off-label promotion.

This is an ongoing story but it could have some major implications for pharma and medical affairs.  Stay tuned to this space for more developments as they occur.

Any comments or thoughts on today’s news?  Click here to share them.

Topic 39: House Clears 21st Century Cures Act – What could it mean for MA and CD?

As we have alluded to before, the House and Senate have been considering another tweaking of regulations related to pharma as part of the broad 21st Century Cures Act (Act). The House has taken a big step forward by approving on a bi-partisan basis the Act. Most of the headlines are focused on the increase in NIH funding, but for pharma people there is a lot of interesting suggested changes in the regulatory environment. NOTE: this is just the House version, the Senate will not take up the bill to later this year so we don’t know if any of these changes will come to pass – so far at least the White House is not threatening a veto.

You can find the whole bill here.

Medical Affairs: All about off label communication

Act Requirement:

Subsection 2102 explicitly requires the regulatory clarification about acceptable dissemination of off-label information:
Not later than 18 months after the date of enactment of this Act, the Secretary of Health and Human Services shall issue draft guidance on facilitating the responsible dissemination of truthful and non-misleading scientific and medical information not included in the approved labeling of drugs and devices.

Implication for MA:

While conceivably once this guidance is issued anyone (commercial and medical) from the company can share off-label information, if the guidelines are anything like the guidance provided by the FDA in their response to the Amarin lawsuit which we discussed here that guidance will explicitly require that the information be discussed by someone from the company with “… the appropriate background or training to accurately communicate scientific information.”
So, conservatively interpreting that definition, if this act passes MA should finally have clear guidelines on how to proactively discuss off-label information. A BIG win for MA.

Clinical Development and Medical Affairs: Support for innovation in clinical trials

Act Requirements:

There are a number of requirements that could be clarified by the Act. I will highlight a few I think are most impactful.
The first is section 2021 which discusses the use of biomarkers. It establishes a process whereby biomedical research consortia can identify and agree upon biomarkers, then submit those biomarkers to the FDA for their review and approval, and once approved can be used by industry as surrogate endpoint. Draft guidance on this process is due no later than 24 months after enactment.

The second is subsection 2061, focused on broader use of adaptive trial design and Bayesian statistics. The Act requires the FDA to update and finalize the guidance on adaptive trial design within 18 months and issue draft guidance on the use of Bayesian statistical models within 48 months. So not exactly pushing the envelope on the Bayesian timeline for draft guidance.

The next is subsection 2062 deals with the use of “real world” observational / registry / safety data in the application for additional indications or to meet post-approval requirements. It requires that a program for the use of this type of data in these ways be established within 24 months including delineating when this type of data will be acceptable to the FDA, the standards and methods needed to be followed when collecting this data. One year after the program is up and running draft guidance is due and then a year after that final guidance is due.

Implications for CD MA

The implications of the acceptance of biomarkers as acceptable surrogate endpoints should have huge implications. Currently these endpoints are gathered but are not relied upon for fear that they will not be acceptable. Knowing in advance that they will be acceptable to the FDA will allow for much more streamlined data collection efforts.

Further clarity on adaptive trial design will be helpful but not earth-shattering. Adaptive trial design draft guidance already exists so all the act is really doing to pushing to get it out of the draft phase and finalized which should reduce risk and make adaptive trial designs more acceptable to less risk-tolerant organizations. This will hopefully push into becoming a standard in P2 trials, reducing the need for multiple trials. I’m not really qualified to discuss how the Bayesian statistical model impact development – if you understand this better than me please leave a note in the comments.

The “real world” data requirement, assuming it produces clear definitions from the FDA about the qualities that the data has to have to be acceptable, could be a dual edged sword. On the one hand, if they have very high expectations about the quality and cleanliness of this data in some cases, especially registries, it could raise the costs. On the other hand, clear definition of what data will be acceptable for additional indication applications will allow for the use of this data more broadly and thus more of these studies to be conducted, which is great overall for pharma.

I am curious to know what you think. Please leave a comment here.

Topic 38 – FDA Comments on Off-label Dissemination – Did it just tip its hand on upcoming off-label policy?

Have you had the opportunity to follow the Amarin lawsuit against the FDA?  If not, a quick recap:

 Amarin is literally a fish-oil salesman – they have fish-oil pills that are already FDA approved for the treatment of very high levels of triglycerides.  They had conducted clinical trials to expand their label to patients with lower levels of high triglycerides.  The FDA rejected their application.  Amarin decided it wanted to share the results of those studies anyway since they were positive and sued the FDA for the right to share its data on off-label use.

The interesting part comes from the FDA response letter.  Putting aside their primary concern that Amarin failed to work with them before suing them, the letter signed by Janet Woodcock went on to layout the condition in which Amarin (or for that matter any pharam company) can share off-label data.

First, the letter reiterated what we already know and have discussed: the reprint exemption to off label communication – distribute reprints from peer-reviewed journals, avoid some simple issues like highlighting only the “good” passages, and you are in the clear.

But then the letter goes on to say that Amarin can also write up and distribute its own summary of the results of their trial if the write up:

  • Remains factual and does not omit material information or introduce bias
  • Includes full data for each treatment group
  • States that the current label does not approve of the use
  • States that the impact on the off-label use has not been determined
  • Shares data about other, known similar studies that may have different results
  • Any financial or affiliation biases between the firm and the people who conducted the study

They go on to add that to protect against being misleading the company should:

  • Provide a copy of the current Package Insert
  • Provide a copy of any relevant reprints
  • Discuss these topics in an educational or scientific setting and not as a part of a promotional discussion or attached to promotional materials
  • Discussions should be conducted by persons with the appropriate background or training to accurately communicate scientific information

While that is still a lot of hurdles, that is a long way from reprints only.  And while these are NOT an official policy now, I think this is telegraphing what we should expect to see in the upcoming policies.

I particularly like the final bullet point which makes it clear that these topics need to be discussed by roles that sound very much like MSLs.

To speculate, if the FDA were to allow establish this as the policy, it would surely free up MA to proactively share both off label and label supportive information.  That would be a big improvement for some MA organizations that deny all proactive sharing of off-label information.

You can find the letter HERE.  The juicy bits begin on page 8.

What do you think?  Click here to leave a comment.

Topic 37: Medical Affairs and the Integrated Payer / Provider Model

For a while we have been discussing the need for a specialized medical affairs function focused on Payers – we discussed it here.

But what about Accountable Care Organizations (ACOs) or other integrated payer / provider models, where the provider owns both the cost and the outcomes of their work. This type of model is becoming more and more prevalent, yet most MA organization have not flexed to directly engage with these types of organizations.

The needs for these organization are not a match for current MSL field organizations focused on HCPs and, while payer oriented organizations may be better suited, they are not a perfect match either.  Like payers, these groups are interested in population-level information. And, like payers, they care about total cost of care. But like HCPs they also place a greater emphasis on understanding treatments in the context of the overall disease progression and methodologies for approaches for ensuring improved outcomes with existing treatments.

I suggest that MA organizations are going to need to develop groups that directly target these ACOs. These will be teams that understand population health and quality metrics.And MA is going to need to collect this population data directly.  One thing that seems clear is that HEOR secondary endpoints gathered during P3 simply lack credibility with these audiences since they know the P3 had inclusion/exclusion criteria that did not model their patient population. Real world data and post marketing studies, already important for payers, is going to be equally important for these ACOs.

MA is going to need to come to them with models of costs and outcomes and budget impact, then partner with them to validate the model and gather relevant data about treatment approaches which produce the best results for the least costs.

What do you think? Leave a comment by clicking here.

Topic 36 – Off-Label Promotion Prosecution is Changing – and Medical Affairs Should Benefit

Normal disclaimer: I am not a lawyer just a lay observer.

I was at the 3rd Annual World Congress Summit on the Evolving Role of Medical Affairs.  As in the last two years, one of the highlights is the presentation by a representative of the OIG and US States Attorney on Off-Label Promotion.

Usually this is an opportunity for them to remind us that pharma is not allowed to promote off label, trot out examples of people who were prosecuted for off-label promotions (which are almost exclusively Sales and Marketing examples, not MA examples) and then encourage us to snitch on our organizations if we think we see this behavior.

But this year was different.  This year we were all introduced to an important new term – Off-label Plus.  What does Off-label Plus mean?  It’s how they refer to cases that they are willing to prosecute.  In light of the Caronia ruling (an overview of which you can find here, with subsequent commentary here and here), they are no longer willing to base cases on simply promoting off label (assuming the test laid out in Caronia that the off-label information presented is from a credible, unbiased source, like a “real” journal, and the presentation is not misleading).  Instead, they are only willing to go after cases where there is Off-Label Plus something else, like Kickbacks or Fraud of some type.

In my opinion this is huge for medical affairs – most medical affairs organizations are unwilling to proactively share even an article published in the NEJM if it is off-label out of fear of being accused of promoting off-label.  Instead we wait to be asked, since responding to a question is not promotion.  I think the fear of promotion is now unjustified.

The simple reality is that even before Caronia no medical affairs employee has ever been prosecuted for simply providing accurate, non-misleading off-label information.  Caronia  was a sales guy, not medical affairs. The only example that the prosecutor could cite of an MA employee being prosecuted was a device company where the medical affairs lead used speaking fees as a kick backs.   Now that Caronia is out there, I think the risk is even lower.

Just like our treatments, all of medical affairs is a risk / benefit.  If we wanted zero risk, we would not have medical affairs or sales or marketing for that matter.  Instead we reduce our risks through the use of strong processes and a compliance function to ensure those processes remain in place.  It is my assertion that providing credible, non-misleading peer-reviewed published off-label data pro-actively is no longer a major risk, assuming there are procedures in place to avoid all the other “Plus” activities.

I don’t expect this to change overnight, but some organizations are going to start operating this way and when the sky does not fall, all medical affairs organizations will be operating this way – my guess is within 5 years.  And this is all for the best – its good for HCPs because they will have the latest information, its good for patients because their HCPs will be well informed and its good for medical affairs because it allows us to do our jobs even better than today.

What do you think?  Leave a comment by clicking here.

Post 35: Trends in Data Sciences for Medical Affairs

Data has always been the backbone of medical affairs. Understanding the data that underlies the company’s products and the products of the competition and understanding the prevalence and treatment data available about the disease state has always been a requirement. And, being able to summarize and explain the meaning of the data is one of the greatest values that MA brings to the organization.

But as a generator of data analysis and manager of data, most MA organizations have been passengers not drivers. Most data sets are being generated by clinical development and analyzed by statistical staff within the clinical function. Even after the product is on the market and the data generation turns from a clinical responsibility to a medical responsibility, most MA organizations still rely on these resources or the resources of outsourcers to define, manage and analyze their data.

However, as MA groups grow more sophisticated in their use of data, and as real world data sets available for analysis continue to increase in size and importance, it may become in the best interest of MA to begin developing some data science capability of their own.

MA Stats

Some MA organization already have their own stats staff or stats staff assigned to them but working in clinical, but in my experience this is still the exception not the rule. Instead, most organization rely on stats people internally who are not primarily focused on MA or on outsourced stats resources. There are a number of challenges with this environment. First, for the internally loaned people, most of them are not that familiar with what MA does and they are also usually not familiar with using real world data sets. Leveraging them requires bringing them up the learning curve, sometimes at the expense of time and effectiveness of the analysis.

Relying on to a large degree on outside statistical help is also very problematic. In these outsourcing situations, the cost can be high and the learning curve that you are paying for becomes the property of the outsourcer to resell to your competition. Additionally, when a non-stats person hires and manages a stats outsourcer, it is very difficult for them to understand if they are getting the best thinking out of the outsourcer and suggest other alternate directions if they feel the outsourcer is taking a less than optimal path. It is this very difficulty that led many clinical organizations, even virtual clinical organizations, to realize that they always needed some stats capability in-house, even if it was simply to manage the outsourcers. Finally, working with outsourcers makes it very difficult to answer quick, smaller “what if” questions that always seem to come up after the main analysis is complete.

Given the importance of these analysis for MA and the need to be flexible, I believe that more and more MA organizations will realize that they need their own stats capability on the MA team – focused full time on the data sets and analyses that are most relevant to the post-marketing world.

MA Data Managers

While some MA organizations already have stats, I have yet to see one that has their own data management function. Nevertheless, I am going to suggest that this will be less rare in the future. Data managers are responsible for the “care and feeding” of the databases that the stats team analyzes. A common function on clinical.

As medical affairs becomes more data sophisticated and as cutting edge groups decide to build huge repositories of real world data to perform ongoing analysis, the need for professional MA focused data managers will grow. These data managers will be more focused on the collating and cleaning of external data then their clinical counterparts and that is why I think the need for an MA specialist group will take hold.

What do you think? Does your MA team have its own stats function today? Is data sciences in the plans for the future? If you would like to leave a comment, click here and scroll down.

Topic 34: New FDA Consumer Advertisement Guidance and Potential MA Impact

Have you seen the new FDA guidance about disclosing risk in consumer-directed print advertising that came out in February? (You can see it here) Unless you are a gluten for FDA guidance-reading punishment, my guess is that you skipped this one since it seems to be commercially focused.

BUT, there is actually something that MA should be aware of and perhaps an opportunity to add some value to our commercial brethren. The focus of the guidance is straight forward – under current law print advertising has to also disclose risks, and the safest approach for disclosing that risk is to publish the full package insert (PI) along with the print ad. As we know PIs are a tough read normally, but when shrunk down to fit in a magazine they are almost unreadable and certainly mostly incomprehensible to the very audience they are supposed to be protecting – consumers.

This has not been lost on the FDA and the guidance linked to above was entirely focused on resolving this issue.

In an FDA survey, few respondents reported reading half or more of the brief summary presented in the traditional format. Of those who read at least some of the brief summary, 55 percent described it as hard to read. Over 40 percent of respondents in the survey reported they do not usually read any of the brief summary in direct-to-consumer prescription drug print advertisements.

The FDA realizes that the full PI is aimed at medical professionals and full of details that the vast majority of consumers don’t care about like clinical pharmacology or chemistry. So the FDA is suggesting that manufactures should have the flexibility to replace the PI with something they are now calling “consumer brief summary.”

What is a consumer brief summary? Per the guidance it is an explanation written in consumer-friendly language (ie. drowsiness not somnolence) that includes:

  • Boxed warnings
  • All contraindications
  • Certain information regarding Warnings and Precautions:
    • The most clinically significant information from the Warnings and Precautions section(s) of the PI;
    • Information that would affect a decision to prescribe or take a drug;
    • Monitoring or laboratory tests that may be needed;
    • Special precautions not set forth in other parts of the PI;
    • Measures that can be taken to prevent or mitigate harm
  • Most frequently occurring Adverse Reaction, and those ARs that are serious or that lead to discontinuation of use, and the severity of the risk
  • Indications for use
  • Significant drug interactions

And this is where Medical Affairs comes into play. Now our commercial colleagues and their agencies are going to be needing to develop information that includes medical judgement, like:

  • What is the most clinical significant information?
  • Why is that information considered most clinically significant?
  • How do practitioners view what is most clinically significant?
  • What information should affect the decision to take or prescribe the drug?

These questions are great ones for Medical Affairs to either provide guidance, answer directly or gather information from practitioners during their interactions to answer these questions and others. Given the proper but strong firewalls between MA and commercial, this new guidance provides a value-added opportunity for MA to provide some guidance to commercial.

MA leaders may wish to discuss this topic with their commercial colleagues.

Do you have any thoughts on the new guidance? Leave them in the comments by clicking HERE and scrolling down to the comment box.

Topic 33: Significant Future Risk of Naming and Shaming in Clinical Trial Results Posting

The Problem

We have talked a lot about big data on this blog, and that’s because it’s a game changer.

As evidence, did you see this article in the NEJM? It’s a research analysis in which they pulled the entire ClinicalTrials.gov database and analyzed it to determine who has been publishing summarized clinical trials results as required by FDAAA from 2007. This analysis was done by cardiologists at Duke, and what got the headlines was that only 38% of completed studies had their data posted as required by the law.

However, dig a little deeper and with more of our focus and you can learn some interesting things about the biopharma industry. Of all the 13,300 (all numbers rough for discussion purposes) completed clinical trials analyzed, 66% were industry sponsored or roughly 8700 trials. Only 5100 of the 13,300 completed clinical trials reported any results, and of 3600 of those 5100 reporting trials, or 71%, were industry trials. So, in a world of terrible compliance, industry was punching above its weight. That still leaves some 5100 industry trials with not results posted despite the law.

BUT, you say, isn’t there some exception for holding back results until after FDA approval/rejection. Yes, a company can file a certificate which allows it to delay posting results in that circumstances. Of the 5100 completed industry trials missing data only 2000 certificates were filed – leaving 3100 or 36% of all industry trials unreported or uncertified per the law.

This is where big data and company reputation risk raises its ugly head. There are big data sources already out there that read all the data from ClinicalTrials.gov. With today’s big data tools it is a straight forward exercise to determine which industry company sponsored which trial and whether it reported/certified per the law. They will also know which products have failed to report/certify if the products are approved. It is not long from now that some reporter will put this together and produce a list of the “best and worst biopharma companies for publishing results” – some uncharitable media outlets (and which ones are charitable to biopharma) may even imply sinister intent at “denying their legal obligation to share this data – what are they hiding.”

Implications for Medical Affairs and Clinical Development

There is a unique opportunity to head this potential distraction off at the pass. We don’t want our MA field team’s spending time justifying why the company is not posting data.

While maintaining ClinicalTrials.gov is generally the responsibility of the CD in most organizations, MA has a strong vested interest to ensuring that the company is bullet proof in this area. MA and CD need to collaborate to make sure that data is posted or the certificates are filed. A process audit to confirm that the processes are in place and are working, as well as verifying that the company does not have any missing posting or filings, is a small bit of work that can save a huge amount of distraction for the entire organization in the future.

What has been your experience in this area? Leave a comment

Topic 32: Big Data in MA – Revisited

Overview

A couple of years ago I wrote a post (check it out here) on the emergence of big data for Medical Affairs. Given the rapid evolution of big data, two years is a long time ago so it’s worth revisiting this topic.

Let’s recap what we mean by “big data.” It is a broad concept, but for our discussion today we will be using big data to refer to the new capability to pull together huge quantities of data that were not directly generated for the purpose they are now being applied. Biopharma has excelled at generating proprietary data sets for a specific purpose, but big data take advantage of non-proprietary data that was generated for a different purpose by applying it in a new way.
These external data sources range in structure, format and value. The real trick to big data is pulling the data from disparate sources, efficiently cleaning it and standardizing it to allow it to be cross-referenced, then finding novel ways to use it.

Example of Big Data in MA

In the last couple of years we have seen examples of companies set up to provide big data services to MA. I will single out one here as an example, but this is not intended as an endorsement. I have no relationship with this company or practical experience with their products.

The company, Med’meme, is a case study of big data in MA. Based on their website, Med’meme takes large, public data sets – in this case lists of scientific presentations from medical meetings and peer-reviewed journals and clinical trial information at least – and in their backroom they apparently standardize it to make all those data cross referenceable. How well they do this, how complete and how accurate the data is, I can’t say. But, when you think about that data source as an MA professional I am sure you are jumping to a bunch of potential uses – like the ability to rank KOLs, to identify new KOLs, to track TA trends in publishing, to identify potential investigators, to be alerted to new publication identification, etc.

And that is the beauty of big data – there does not appear to be anything in their data set that has not been available (with some costs) to biopharma for years. Their service is finding a way to scrape it all together, standardize it and allow it to be searched effectively.

Buy v Build in Big Data

When I first published the article about big data I had a number of “buy vs. build” questions. The reality of big data in its current form is about re-using publically available data in novel ways, so building it internally is unlikely to produce proprietary value. However, combining these data sets with proprietary data, or asking interesting and unique questions of the data is something that can remain proprietary – so some hybrid solutions may be valuable.

If big data is not a part of the MA information technology planning it should be.  This capability represents an opportunity for strategic advantage in the short-term until it is widely adopted.

Conclusion

Big data is a new reality. A huge new data set, the Sunshine Act database, has just come on-line, and other data sources are increasingly making their data available for these types of analysis. Expect to see major development in this area in the coming couple of years.

What has been your experience with big data in MA? Leave a comment.

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