Bart’s Corner: Drug Safety Stress Tests

Nov 25, 2014

Pharmacovigilance, Drug Safety and Regulatory Affairs Author & Expert

Telerx Blog: Drug Safety Stress Tests

In the world of banking and finance, the US government and the EU have been doing “stress tests” on banks ever since the 2008 financial crises.

These are defined, on Wikpedia, as:

“Regulators devise hypothetical future adverse economic scenarios to test banks. These established scenarios are then given to the banks in their jurisdiction and tests are run, under the close supervision of the regulator. They evaluate if the bank could endure the given adverse economic scenario, survive in business, and most importantly, continue to actively lend to households and business. If it is calculated that the bank can absorb the loss, and still meet the minimum bank capital requirements to remain in active business, they are deemed to have passed.”

The concept is worth considering in drug safety and pharmacovigilance (PV), though referring to various extreme business and health scenarios (not financial ones) that might occur but are unlikely.

To put this into our world: Could your drug safety department withstand a crisis or a “perfect storm” that puts severe stress on your department and company?

Stresses on Drug Safety/Pharmacovigilance from a Company or a Regulator’s point of view:

  • Massive number of adverse events (AEs): Or worse, serious adverse events (SAEs) that occur in a short space of time. In this scenario, a company or a health agency (HA) DS/PV department is overwhelmed by a sudden surge in cases. This could be from a clinical trial or, more likely, a marketed product, perhaps right after launch when many unexpected SAEs occur. This could be due to a product quality problem with the drug, unexpected new use in a vulnerable or at risk patient population, an intercurrent illness (e.g. the flu) that gets reported as possible AEs or other easily imaginable circumstances. It could be due to “secular effects” (e.g. a celebrity praises or pans the drug or has a bad SAE) which go viral on the internet and in various social media sites. Sometimes this is predictable (e.g. an influenza drug will have more AEs during flu season or an allergy drug during high pollen season), but oftentimes not at all predictable.
  • Sudden recall or market withdrawal: This may be due to a product quality problem forcing the recall of a large number of drugs or devices. The author saw this happen when, many years ago, nearly a million inhalers used in acute asthma were recalled across the US (and some countries abroad) when active product was found to be missing from a few canisters. This produced the perfect storm of many AEs, hundreds of thousands of returned canisters and intense HA and press interest followed not long thereafter with intense lawyer interest!
  • Tampering: This can be an enormous problem involving not just adverse events, product quality issues, product returns and HA intensive involvement but also the police and FBI. The public health issue is paramount and requires immediate action. The classic example of this was the acetaminophen tampering issue years ago. Smaller scale tampering issues have occurred more recently. Counterfeiting is a similar problem which may be harder to handle for companies as they do not have control of the counterfeit product.
  • HA audit or inspection: Particularly if unannounced (as the FDA usually does). If the company is unprepared or in busy season or has key personnel out of the office, a clear short-term stress can occur. In this scenario, the company must respond immediately. One cannot ask the FDA to return in a couple of weeks when the key players return! The author once saw a situation where a scheduled EU audit was underway in the US and the FDA arrived the same day! Fortunately, the FDA, in this case, agreed to postpone their inspection.
  • Change of some sort in the company: This can be a change in management (e.g. a new head of drug safety), the arrival of someone in a non-PV senior position who has “unique and interesting ideas” on how to do PV which are highly unorthodox and often unwise. For example, the author remembers a new senior attorney arriving in the company who felt it was important that all MedWatch forms sent to FDA should be reviewed and approved by the Legal Department. Not only was this problematic from the regulatory/legal point of view, but the Legal Department did not realize they would have to do nearly immediate review and turnover of enormous numbers of cases within 24 or 48 hours to adhere to the timelines and work flow.
  • Decision to outsource or change vendors: Some drug safety or related functions are suddenly changed. For example, call centers and medical information are rarely run by DS/PV but handle some key DS/PV duties such as initial case receipt and intake of new SAEs. The decision to change methodology, prioritization of SAE cases, out-sourcing (with or without off-shoring) can suddenly throw a smooth-running operation into disarray or worse. The author recalls when this function, which was in the US, was suddenly moved abroad to a country that did not have native English or Spanish speakers.
  • Change in corporate structure, takeover, etc.: Sometimes the mere announcement of a takeover or sale will induce members of many departments, including DS/PV, to start looking for new jobs or to retire. When the actual merger or change does occur, all sorts of operational issues arise. Will the two DS/PV departments be merged or stay separate? Will they use one or two databases? Who will run things? Will there be layoffs and cutbacks (the answer to this one is usually yes, the key question is when and who)? This certainly is a stress.
  • Announcement that the company’s safety database will no longer be supported by the vendor: This actually happened several years ago when the IT company that created, maintained and supported one of the major safety databases used in the US announced it was stopping support. Although this was not an acute issue as their exit from the field was over a year down the road, it did produce a major issue as companies using this software had to decide whether to maintain and update it themselves or switch to a new database.
  • Moving to a new safety database: In a similar vein, moving large amounts of data from one safety database to another, even for sound business reasons, can be a nightmare if millions of cases and billions of data points are involved. Although, in theory, this can be planned and controlled, it is a highly stressful time. In particular, the day the switchover occurs can be traumatic, particularly if the change is irreversible and one cannot return to the old database if problems occur. Having been through this several times, with both large and small amounts of data, this author can say it is never pleasant or without stress.
  • Acquisition of a new drug or drugs: This may suddenly produce quantitative issues (more cases) as well as qualitative issues (new drugs that need to be learned) and possibly new workflow arrangements. Although one hopes these can be planned in advance, this is a stressful time.
  • Lawsuits: When a lawsuit occurs in regard to SAEs/AEs, it sometimes occurs that the DS/PV department’s documents (and computer files) are “locked” by legal as these documents and files may need to be supplied to the other side in the lawsuit as part of “discovery.” Sometimes, in handling SAEs, the DS/PV department cannot directly contact patients or health care professionals as they normally do for follow-up, but may have to send all communications through the company’s legal department first – enormously complicating the process. In addition, if the DS/PV department has to search for documents, give testimony or appear at depositions or confer with the legal staff, this can be quite stressful and disruptive.
  • Re-engineering: Sometimes companies go through the painful process of redoing the entire or large parts of the DS/PV department to streamline and modernize processes. This is common in many business and other institutions when technology, regulations and other things change making the old ways no longer very effective. Again, this can and should be planned in advance but even so, it can significantly increase the workload and add on stress.
  • Major changes in the regulations: In 2012, the EU massively changed its post-marketing requirements by putting in place the Good PV Practices modules. Many things changed and some things changed quite quickly. Many of the EU countries’ health agencies and IT infrastructure were not ready and interim systems were (and still are) put in place.

What To Do

Some stresses cannot be predicted. These are “unknown unknowns” or “black swans” (“a metaphor that describes an event that comes as a surprise, has a major effect, and is often inappropriately rationalized after the fact with the benefit of hindsight.” From Wikipedia. Read Nassim Nicholas Taleb’s book the Black Swan for more on this.).

Normally then, one cannot prepare for these black swans in advance. Other stresses can be predicted and mechanisms should be put in place to minimize the stresses, problems, volumes, etc. To do this, the DS/PV department should stay up to date on corporate, regulatory, research, marketing and other events that will touch upon them. This is broadly described as “DS/PV Intelligence.” This means reading the internet, the trade websites and journals, attending conferences, keeping politically in tune within and outside the company etc.

The DS/PV department should function well in normal times. This should be ascertained by regular internal (and/or external third party) PV audits. Any CAPAs that need to be put in place should be done so and completed rapidly. SOPs should be reviewed and revised as needed. Training should keep everyone up to date.

There should be a business continuity/crisis management SOP that, at the very least, recognizes that crises occur and a mechanism will be invoked, at a moment’s notice, to respond in a rational way. A spreadsheet of key players who can be immediately contacted should be maintained and kept up to date and owned by someone.

As in war, detailed plans may be drawn up in advance, but when the crisis does hit, there is a lot improvisation that will be needed. The best one can do is put all the mechanisms in place to be invoked when the blow does hit. Or to put it in the terms at the beginning of this posting, if you can, do a stress test. Periodically, say yearly or every 6 months, hold a meeting or two with the key stakeholders to anticipate stresses and problems that may occur and outline a response.

Do a thought experiment seeing how the company and the department would react to each of the stresses listed here or other stresses you devise yourself. If the response seems reasonable and doable, fine. If there seem to be gaps, they should be filled.

This list is not meant to be complete. There are many other stresses that can befall the DS/PV folks. If you have any that do not fall into the above categories, by all means drop us a note and add to this list. And if you have any wisdom or advice to add, by all means let us know!




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