Safety Items in the News

Feb 27, 2014
Bart Cobert

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Several safety items have been in the news recently and are summarized here.

Direct-To-Consumer Safety

In February the FDA published a notice in the Federal Register (see: entitled: “Disclosure Regarding Additional Risks in Direct-to-Consumer (DTC) Prescription Drug Television Advertisements”.   The FDA is requesting comments within 60 days.

This is a proposed study on direct to consumer advertising on TV and radio.  FDA is concerned that the current mechanism of DTC advertising produces statements on the air that are too long and are poorly comprehended leading to “therapeutic noncompliance due to fear of side effects.” Yet there is also concern that the ads do not contain adequate risk information.  A proposal is that risks mentioned in the ad should be limited to those that are serious and actionable with a comment that there are other risks not included in the ad.  A statement to the effect: “This is not a full list of risks and side effects. Talk to your doctor and read the patient labeling for [drug name] before starting it.”  This announcement indicates that FDA will do a study of these proposed possible changes by surveying consumers using the internet.  This will most probably lead to some changes in the way DTC advertising is regulated by FDA.  They plan to survey some 15,000 consumers.  There is no time frame on this but one would suppose that this will take about a year or more to complete and then the results will probably be put into new draft regulations.  The entire process may indeed take a couple of years.

Comment: From a safety perspective, DTC advertising has always been problematic.  These ads carry long announcements of possible adverse events, some of which are gruesome and may fail to put the risks in perspective.  Obviously in a 30 or 60 second spot that is aimed at selling the product, the disclosure of bad things is done because of required regulations.  What is interesting is observing products that have gone from Rx status to OTC and are advertised on TV.  Before the change to OTC, there was a long and detailed package insert noting some significant risks.  When the product goes OTC, the new labeling is no longer the package insert but “Drug Facts” section on the packaging which only includes a few, usually minor, adverse events.  See, for example, labeling for anti-histamines or smoking cessation products.

EMA PV Assessment Fees

The EU has more or less agreed and finalized the fee schedule for PV assessment procedures at the EU level.  (See:

The fees will be:

  • PSUR/PBRER assessment will be €19,500 (~$26,000)
  • Post-authorisation assessment studies (PASS) will be €43,000 (~$56,000)
  • Assessment of referrals initiated as a result of PV data from €179,000 to €295,000 (~$238,000 to $383,000)
  • An annual flat fee of €67 for each pharmaceutical form (e.g. tablets, drops, injectables etc.) authorized at the national level.

There will be a 40% reduction for small and medium sized companies and “micro-enterprises” will be exempt from any fees.  This agreement needs still to be formally approved by the EU Parliament and the Council after the text has been revised by “the lawyer-linguists”.  Not surprisingly, the industry has objected.  (See for example:

Comment:  Over the last several decades in many regions of the world, the US and EU in particular, the concept of user fees has increased.  This is aimed at making those who use a particular government service pay for it directly rather than using general tax revenues.  This has been in place for many years on highways, for example, where drives pay tolls on bridges or autoroutes.  This spread in the US in 1992 when the FDA introduced user fees on industry (PDUFA).  Originally safety was not covered by fees but this has changed.  From a societal, utilitarian point of view this is not unreasonable.  However, now that the fees are increasing significantly it is likely that at some point these fees will enter into business decisions on whether to develop particular drugs if there are de facto price controls (e.g. the government sets reimbursement) and regulatory fees, it may reach the point where it is not worth developing a drug.  For example, a drug that is approved and needs a PBRER every six months will cost over $100,000 for PBRER review on top of filing fees and other regulatory costs.  At some point, one will wonder whether the fees are set to only cover costs of review or rather are used to raise revenue for other uses.

Universities sued over drug safety

An interesting article in “” was published in February.  (See news story covers a trial starting in Illinois over the drug Pradaxa by Boehringer Ingelheim.  The issue revolves around the RE-LY trial which was the key study used for FDA approval.  The issue now revolves around the safety of Pradaxa.  This lawsuit, in the US, claims that McMaster University and Hamilton Health Sciences (both Canadian institutions) and another institution failed to adequately design and administer the trial, failed to maintain data and failed to report serious adverse events.

What is most interesting in this lawsuit is that these are non-US institutions being sued in the US, that safety concerns in the post-marketing arena are now being reflected back to the clinical trials done years before, that conceivably many institutions could be sued (in the RE-LY trial there were 18,000 patients enrolled in 44 countries according to this article, and that the FDA is actively looking into the safety of the drug with a review of post-marketing in its database(s).

Comment: This is a fascinating case that may alter the way clinical research will be done in the future.  It suggests that universities, both in the US and elsewhere, as well as clinical researchers might be sued and possibly held liable for safety issues if there are defects that can be proven in court in regard to the design and operational aspects of the study as well as safety reporting.  It reinforces the concepts that clinical trials with human beings must be done impeccably with the appropriate study design, good clinical practices, careful monitoring and, of course, complete and timely safety reporting.  One wonders if risk-based monitoring which is now becoming more popular will be touched by this.  This will be a fascinating suit to watch as it unfolds.  See the referenced article above for a detailed summary.

FDA and EMA Collaboration

The FDA and EMA announced in February (See that they are setting up a new set of regular collaborative meetings (called in their jargon “clusters”) between the EMA other regulators outside the EU including FDA, Health Canada and the Japanese Pharmaceuticals and Medical Devices Agency.  There are already such FDA/EMA collaborations (clusters) covering biosimilars, oncologic drugs, orphan medicines and blood based products.

The FDA and EMA will now have monthly teleconferences to exchange information on safety and to coordinate activities.

Comment: Nothing surprising here.  FDA and EMA as well as other health agencies have been collaborating for years on both formal and informal levels.  This agreement now continues FDA’s outreach and globalization efforts, particularly since the major source of most drugs in the US and EU is now Asia (India and China in particular).  Everything is now interconnected and we can expect to see widening efforts between and amongst governments as well as the use of the internet, social media and big data to improve safety.  It will be interesting to see how this plays out.  Things will change now rapidly.

New Method for OTC Approval

Finally, FDA has announced that they will now start a  new initiative to look at how over-the-counter drugs are approved for marketing.  Dr. Woodcock of the FDA has said that “The current system isn’t working well for the public or for us”.  No details yet but this suggests that the so-called Monograph system of approval will be replaced or updated.  This will most likely mean tougher requirements for efficacy and safety.  No details are yet available.

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