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29 posts from February 2016

February 29, 2016

FDA Guidance: Determining the Extent of Safety Data Collection Needed in Late-Stage Premarket and Postapproval Clinical Investigations

The FDA finalized a guidance it originally released in 2012 that is aimed to help industry collect safety data in late-stage premarket and postapproval clinical investigations. The FDA says in the guidance that selective safety data collection may be possible for some late-stage premarket and postapproval clinical investigations because "certain aspects of a drug's safety profile will be sufficiently well-established and comprehensive data collection is not needed."

Safety Databases

Safety databases collect information to accurately assess and characterize the risks of a new drug. A sponsor collects safety-related data during the course of drug development and knowledge of a drug's safety profile can change as more information comes in through its lifecycle. However, FDA notes that encouraging selective safety data collection in late-stage premarket and postapproval clinical investigations is consistent with the agency's approach to safety assessment which is focused on information that is useful and adds to current knowledge.

FDA outlines the growing interest in larger, simpler trials to obtain outcome data, data on long-term effects of drugs, and data on comparative effectiveness and safety. According to the agency, excessive safety data collection may discourage the conduct of these types of trials by increasing the resources needed to perform them and be a disincentive to investigator and patient participation in clinical trials. Therefore, FDA believes its guidance will facilitate the conduct of larger trials without compromising the integrity and the validity of trial results or losing important information, facilitate investigators' and patients' participation in clinical trials, and help contain costs by making more-efficient use of clinical trial resources.

Selective Safety Data Collection

FDA issues several examples of selective safety data collection, including no collection of certain safety data, less-frequent collection of certain safety data, and collection of certain safety data from only a fraction of the total trial enrollment. The agency writes that in general, selective data may be appropriate for certain types of safety data if:

  • The number of patients and their characteristics, the duration of exposure, and the dose range used in previous clinical investigations are sufficient to adequately characterize the safety profile of the drug for common, non-serious adverse events.
  • The occurrence of common, non-serious adverse events has been generally similar across multiple clinical investigations.
  • The drug's safety profile is established to the extent that it is reasonable to conclude that the occurrence of common, non-serious adverse events in the population to be studied will be similar to rates observed in previously conducted clinical investigations.

FDA also clarifies when selective safety data collection may be appropriate, noting the following types of clinical investigations:

  • Clinical investigations of new indications of approved drugs, if an existing safety database is relevant to such investigations.
  • Postapproval clinical studies and trials conducted to fulfill postmarketing requirements and postmarketing commitments. For example, when the study population in these types of studies is generally the same as or similar to the population from which the premarket safety database was derived, safety data collection can often be limited to the primary safety endpoint and other endpoints of interest.
  • Late-stage premarket and postapproval outcome clinical trials.
  • Premarket clinical investigations for some original applications, unless sufficient safety data already exist to adequately characterize the safety profile of a drug, comprehensive safety data collection is expected.
  • Postapproval clinical investigations in a different patient population or with different doses or other conditions of use. Selective safety data collection generally may not be appropriate in clinical investigations of marketed drugs in which there are important differences in the patient population, dose, dosage regimen, duration of use or route of administration compared with the conditions of use for the marketed indications.

Additionally, when selective safety data collection is suitable, it may be appropriate to limit collection of data or stop collection of some data, such as:

  • Non-serious adverse events not associated with dose modification, drug discontinuation, or withdrawal from the trial.
  • Routine laboratory monitoring as in many cases it may be possible to eliminate routine laboratory monitoring or to decrease the frequency of monitoring certain laboratory parameters.
  • Information on concomitant medications; if existing data satisfactorily characterize all anticipated drug-drug interactions and metabolic pathways, additional detailed information on concomitant medications may be of limited use, particularly for drugs used only short term.
  • Patient history and physical exams, where less-detailed histories and less-frequent physical exams for patients may be appropriate in some circumstances, especially in outcome clinical trials.


FDA writes that other considerations for safety data collection including the collection of complete safety data in population subsets and collection of complete safety data that identifies risk factors. The guidance also specifies that sponsors should be aware of data types that are generally not appropriate for selective safety data collection and should always be collected. This includes:

  • Data on all serious adverse events.
  • Data on non-serious adverse events that lead to dose modification, drug discontinuation, or withdrawal from the trial.
  • Data on unscheduled study visits, hospitalizations, and accidental injuries because these events may reflect serious adverse events of the drug.
  • In an oncology setting, data from all Grade 3 and Grade 4 adverse events, as well as Grade 2 adverse events that affect vital organs (e.g., heart, liver).
  • In development programs for rare disease indications, complete safety data should be collected, because these trials generally have limited patient populations and are unlikely to meet the recommendations for selective safety data collection.

For these types of safety data, it is generally important to collect information on all occurrences to better understand the following:

  • Causality;
  • Incidence;
  • Severity of adverse events;
  • Populations that are at risk;
  • Dose-response;
  • Other factors that contribute to our understanding of the nature of the event and who is at risk.

In its final section, FDA added language titled, "Agreement between sponsors and FDA on a plan for selective safety data collection." FDA writes that sponsors should discuss its specified plan with the relevant FDA review division or divisions at the appropriate time (e.g., at the end-of-phase II meeting for selective safety data collection for a phase III trial). The agreement reached should be incorporated into the procedures for safety data collection in the protocol, the monitoring plan, and other appropriate trial documents, according to the agency.

February 26, 2016

Recent Study on Population Health Sheds Light on Progress

A recent study provides one of the first, if not the first, in-depth, national look at the pace of transition from fee-for-service to models based on fixed payments linked to outcomes. The study reviewed survey responses from over three hundred executives, and interviews with more than one hundred key decision makers across United States healthcare delivery organizations. The study was done by Numerof & Associates, a healthcare strategy consultancy, and found that most healthcare providers continue to lag in implementing population health management, despite the broad agreement that population health management is important to future market success.

Population health management has increasingly become an important topic of conversation, but little has actually been done. More than half of the respondents to the survey rated population health as "critically important" to the future success of their organization, and nearly all believes that it is more than "somewhat important." However, when asked if their organization was in at least one agreement with a payer that includes some form of upside gain or downside risk, respondents said that 20% or less of their organization's revenues flow through them, leaving population health in the realm of "business model experimentation."

According to Dr. Rita Numerof, president of Numerof & Associates, "U.S. healthcare organizations are entering a period of greater change and disruption than any industry this side of taxicabs. However, our study finds that most providers are still just testing the waters with these models and to date there's still far more talk than action when it comes to population health management." Numerof expects that the push to value will continue to accelerate, since the "wait and see" approach that many organizations have chosen to adopt is quite risky.

Michael Abrams, the managing partner of Numerof & Associates, believes that "[t]he traditional players in the payer, provider, and manufacturer spaces are wrestling simultaneously with not just the question of how to change – but how fast. A select set of leaders are making real progress, but overall we're still a long way from where we need to be."

Dr. David Nash, Dean of the Jefferson College of Population Health, collaborated with Numerof, and stated, "Providers cannot wait any longer to implement the basic infrastructure necessary to practice population based care. Payers cannot wait any longer to grasp the lessons from Medicare experiments and prepare for a world where 'no outcome, no income' will reign supreme.

What Does the Study Tell Us?

During the interviews, some participants talked about "bad memories" from previous healthcare reform efforts, and how those memories and previous experiences are impacting organizational receptivity to change. A vice president of a nationally-recognized academic medical center offered the following during an interview, "We're in the early stages of our population health efforts…However, we're hesitant given previous experiences with capitation. In the 1990s, we aggressively pursued capitated payments, resulting in about $200 million in losses."

Further adding to the hesitance based on previous bad memories, the legacy of mutual distrust and antagonism between providers and payers is slowing the transition to new business models. A COO of a major healthcare network was quoted saying, "Most payers we've engaged are not enthusiastic to partner with us on population health." Barely over half of respondents found that payers are more than "somewhat willing" to enter into cost/quality risk agreements.

The economic incentives are measly, and as such, the study found that when providers are willing to move ahead, it tends to be because they are mission-driven and believe that it is the "right thing to do." Respondents who described their mission statement or culture as the primary driver behind their population health efforts reported a larger proportion of revenue under alternative payment models, contrasted to organizations whose primary motivation is financial or market-based.

Lastly, and somewhat surprisingly, differing definitions of "population health" seems to be holding up progress. Some organizations even reported multiple definitions being used internally, leading to confusion across the organization, and hampering any efforts to make real changes. The authors of the study believe that the internal definition of population health has "real implications for the pace at which the organization can move forward on its value-based initiatives as well as what specific initiatives are prioritized over others."


In sum, despite broad support and agreement among healthcare providers that population health management will be important to their success, there is little to no action being taken. Many providers are worried about getting ahead of the market or facing potential losses, which are valid concerns, but by waiting to make decisions and changes, they might be in jeopardy of not being able to keep up with the shift as it continues to accelerate.

However, given the lag in participation rates, it will likely take either a mandatory program from CMS to get wider participation, or strong incentives from CMS to breathe life back into the idea.

Eighth Annual Compliance Year-in-Review Now Available

The Eighth Annual Compliance Year-in-Review presentation is now available through Potomac River Partners. This presentation is typically the "kickoff" of the CBI Pharmaceutical Compliance Congress, but this year, due to weather related-issues, it was not presented.

The presentation is a comprehensive recap of key compliance events from 2015, including settlements, new laws and guidance, and industry news. According to Potomac River Partners, clients have shared the downloadable presentation with their Board of Directors, Compliance Committee, and other senior-level executives, even sharing the Year in Review at national sales meetings or as part of a live compliance training.

Federal Settlements

One of the first topics the Year in Review presentation broaches is federal settlements. The presentation starts in January 2015 with the $39 million Daiichi-Sankyo settlement to resolve False Claims Act and kickback allegations, and goes through to December with the $39 million Endo settlement, and the Dynasplint Systems $10 million settlement, both resolving False Claims Act allegations. Potomac River Partners kept track of all of their featured settlement by month at the bottom of each slide; therefore, the very last December slide shows all companies who made a settlement to resolve the following non-exhaustive issue list: False Claims Act allegations, Foreign Corrupt Practices Act allegations, kickback allegations, and rebate and marketing issues.

State and Civil Settlements

Potomac River Partners then lists select state settlements, including settlements in states like Texas, Oregon, and New York. That information is followed by an infographic that stacks civil settlements against each other, for an easy way of seeing civil settlement amounts, the companies who settled, and for what allegations.

Changing State Law Landscape

A particularly helpful portion of the presentation is the "Changing State Law Landscape" part. The presentation goes through several states, and alerts readers to the changes that were made, allowing readers to then delve into further research on the changes.

Drug Pricing

It has been a long time, if ever before, since drug pricing has been in the headlines in the ways it has been starting in 2015, starting with Turing's price hike of Daraprim. The presentation shows other companies who also came under fire for pricing issues, and the focus Congress has started to have on the industry as a whole. The presentation also includes a slide that shows which states have introduced, or adopted, new legislation relating to drug pricing.

Other Key Compliance News

The bulk of the presentation closes out with slides on miscellaneous healthcare compliance news, and information on the heightened levels of enforcement worldwide, including countries such as China and Romania. Additionally, there are several slides about international compliance news, touching upon countries like Australia, France, and the entire European Union.

2016 Preview

The last few slides are very small font of many compliance issues that have already begun to take center stage in 2016, highlighting for readers the important issues and what to be on the lookout for as the year progresses.

We encourage our readers to download the Year in Review presentation. If you need to catch up on past years, presentations are available for years 2008 through 2014.


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