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Tag Archives: FDA

Topic 44 – Amarin Settlement and What It Means for MA

We have been following the developments in the Amarin off-label communication case for awhile and you can find our posts that provide background here, here, and here.

In brief, Amarin has an FDA-approved indication to market its fish oil supplement as a treatment for very high triglycerides. It conducted a study that showed it lowered the triglycerides in moderately high patients but the FDA declined to approve the label extension because Amarin failed to prove a link to prevention of coronary artery disease. Amarin then informed the FDA that it intended to communicate the triglyceride lowering data to the market and the FDA informed them that it would consider any such communication off-label promotion. Amarin then sued the FDA for unfair restraint. Amarin was granted an injunction against the FDA, which appealed the decision.

In the latest development, the FDA has settled with Amarin, closing down the appeal before a ruling could be made to set clear precedence. In the settlement, which can read about here, the FDA agreed that Amarin could inform doctors of the studies supporting the fact that its product lowered triglycerides in a range of patients as long as the data presented was truthful.  It also set up an “optional” provision in which Amarin can meet bi-annually with the FDA to review the material that they wish to present to ensure that the FDA will find that information truthful and any disagreements from these discussions would be sent to a court to make the final decision.

The FDA’s perceived fear of a precedence setting ruling is not going to go unnoticed. Already another pharma company, Pacira, is suing the FDA under similar circumstances, which you can read about here.

If this case is also settled, expect to see the floodgates open.

It is more than past due time for the FDA to provide clear guidance to industry on the use of truthful, non-misleading communication of scientifically valid data that is not supported by the label. When that guidance is finally offered, it will be a game changer for MA. We believe that most organizations will realize that the safest way to communicate such scientific data will be through the use of peer-to-peer communication driven by medical science liaison-type roles and this will lead to a major expansion of many MSL groups.

We will continue to follow this story. We would love to know what you think. Leave a comment.

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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 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.

Update: Off Label Free Speech Ruling Left Unchallenged at Appeals Level

As I discussed here, a recent ruling by the Second Circuit Appeals Court provided a new legal foundation for off-label promotion on free-speech grounds.  As the law currently stands in the Second Circuit, as long as the speech is “truthful” it is protected by the First Amendment and thus open to anyone.  Sales reps and MSLs in Ney York, Conn. and Vermont have one less thing to worry about.

Many, myself included, assumed that the FDA would ask for a re-hearing in the Second Circuit, but that date has come and gone without such a request.  You can read about it here.

At this point the FDA can go two ways – they can ignore the ruling and let it stand for the Second Circuit, which may result in a set of haphazard interpretations over time as different Circuit Counts rule differently, or it can appeal the ruling the Supreme Count.  Assuming the Supreme Court would agree to hear the case, appealing it to them could result in a ruling that the Second Circuit ruling should be the law of the land.

So the FDA is left with a choice – take what it has and accept that the off-label promotion rules may gradually crumble or risk those rules completely by appealing to the Supremes.  They have until mid-March (or until mid-May if they wish to extend their timeline) to make that decision.  I will continue to fill you in when I learn more – watch this space!!

OffTopic: The FDA Monitoring and Whistleblowing Scandal

Have you been following this issue?  It gets more and more fascinating the further you dive into it.  A excellent and definitive analysis can be found here, but for those of you too busy to read six small print pages, allow me to summarize:

The Setting:

Late in the 2nd Bush Admin, at the Center for Devices and Radiological Health (CDRH)

The Baseline Concern:

Some first-line reviewers felt that computer-aided cancer screening diagnostics should not have been approved for use based on their interpretation of the risks associated with by-product radiation and their lack of confidence in the data within the application

The Baseline Grievance:

 The first-line reviews saw their recommendations overturned by their senior management, who granted approval.

The Work to Resolve the Grievance:

 The first-line reviews complained to Office of Special Counsel (OSC), OIG,  members of Congress and eventually to the New York Times about the situation.

OK, already a nightmare but at least fairly clear.  Government employees are permitted under the law to ignore certain confidentiality requirements if the safety of the public is at risk.  They are not, however, allowed to disclose non-safety related confidential information publically.  This is where the first line may have been crossed.

The NY Times Gets Involved:

The NY Times publishes an article describing the situation and including certain confidential information contained in the application and that may not have been directly related to safety concerns.

The Companies React:

The companies whose confidential information is now plastered over the front page of the NY Times demands that this stop.

 FDA Senior Management Reacts:

FDA senior management arranges to have the FDA-issued computers of a number of potential leakers secretly monitored – every website visit, every key stroke, every file downloaded.

Quick aside: to be fair to the FDA, every time an employee logs onto their FDA computer they are forced to read the following “You have no reasonable expectation of privacy regarding any communications or data transiting or stored on this information system….”  Seems to me its hard to argue that they did not have fair warning.

FDA Senior Management Finds the Leakers/Whistleblowers:

Some of those first-line responders are clearly found to be communicating with the NY Times and other media outlets.  They also find correspondence with Congress, OSC and OIG.

FDA Senior Management Terminates the Leakers/Whistleblowers:

Over the next couple of years the contracts of the leakers were not renewed.

Leakers/Whistleblowers Sue FDA for Wrongful Termination:

A lawsuit is, of course, already pending on this.

So far this is a really sad situation, but at least understandable.  Now, however, its all about to blow up.

FDA Contractor Screws Up Big Time:

An FDA document management vendor makes a world-class screw up – posting thousand of pages of information that was secretly captured from the computer monitoring on an unsecured website.  A terminated leaker/whistleblower discovers this accidentally while Googling her own name.

Everyone Blows a Gasket:

With the documents revealed, all sorts of groups blow a gasket.  The leakers/whistleblowers claim their rights were infringed.  Congress is furious because some of the communication that was monitored included communication to Congress.  The OSC and the OIG are very upset because some of the communication was to them.  Neither Congress nor OSC/OIG communications are supposed to be monitored.

And this is where we are today.

Frankly, this whole situation is a major fiasco.  It makes the FDA look like the most dysfunctional organization in the government, and that is saying something.  Clearly CDRH needs to be stripped down to the floorboards and rebuilt with a functional culture.

Why am I taking a “blame everyone” perspective instead of supporting the leakers/whistleblowers.  Normally that would be where my heart was at, but it was just released that those same leakers/whistleblowers had filed a secret lawsuit in court against the manufacturers whose products they felt were unsafe.  And this lawsuit was filed while those leakers/whistleblowers were still employed by the FDA reviewing exactly these products.  And those same leakers/whistleblowers demanded at least 15% of what would be a multi-billion dollar settlement.  Not what you would consider an impartial set of reviewers.

So, this is a pox on both houses situation.  We deserve and should expect better from the FDA.

What do you think?  Anything I missed?  Leave your comments below.