Safety is No Accident
Snapshots of DIA 2020 Pharmacovigilance and Risk Management Strategies Conference

Wayne Pereanu
Science Writer

IA’s 2020 Pharmacovigilance and Risk Management Strategies Conference included thirteen sessions that describe the current regulatory environment as well as primary sources of risk. The sessions, together with a keynote talk by Steven Murray (Exponent), provide a foundation for making informed and up-to-date decisions in a pharmacovigilance program.

Key Takeaways

  • New ICH and CIOMS programs are underway to address evolving issues related to patient engagement and safety data collection.
  • The global regulatory framework for pharmacovigilance has evolved in different regions independently and consequently exhibits a regional focus on different areas of safety and pharmacovigilance practice.
  • The regulatory context surrounding risk management tools, such as REMS and RMPs, continues to evolve in a regional manner, making global risk management a challenging endeavor.
  • Current research findings on topics such as DILI and alloCAR-T therapies will have an impact on the benefit-risk analysis associated with these therapies.
  • Several pharmacovigilance approaches are being pursued to help address the growing concern of medication errors.
  • Regulatory safety assessment is making growing use of real-world evidence using novel approaches.

ICH and CIOMS Updates

Michael Richardson (Bristol-Myers Squibb) described the Council for International Organizations of Medical Sciences (CIOMS) as a think tank that takes on “gnarly pharmacovigilance topics” and produces guidelines. Currently, CIOMS is organized into six working groups. Of particular interest, Working Group XI is focused on patient involvement in the development and safe use of medicines. The final expected guidelines from this group will take the form of a pragmatic Points to Consider document that describes the current state of the field, existing initiatives, and upcoming challenges.

One of the significant users of CIOMS guidelines is the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), which often uses the CIOMS guides as a basis for their own guidelines. An update to their E2D Guideline for post-approval safety data management is currently in the works (E2D(R1)) to better use existing data as well as to capture new data, such as social media, that were not available when the guideline was first created.

Regional Regulatory Framework Updates

India’s pharmaceutical market is experiencing a 12-14 percent growth per year. Along with this market growth is concomitant growth in pharmacovigilance requirements for market authorization holders in India, according to J. Vijay Venkatraman (Oviya MedSafe). In Japan, labeling regulations have been revised for the first time in twelve years. Rie Matsui (Pfizer) provided a detailed summary of the revisions and how these changes are in a transition period for the next four years. Finally, China has been accelerating its pace of regulatory reform to follow ICH guidelines, after joining ICH in 2017. Stella Xu (dMed) described the implementation plans and standards that China is establishing, in particular updates to the E2B(R3) specification for electronic submission of post-marketing safety reports.

The practical ramifications of what a UK withdrawal (Brexit) means for European pharmacovigilance is a hot topic. These effects include such administrative changes as moving the headquarters of the European Medicines Agency (EMA) from London to Amsterdam. But withdrawal also has potentially patient-impacting consequences, such as the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) losing voting rights in EU regulatory decision-making processes. Sarah Vaughan (MHRA) described how the UK will continue to focus on patient health after the implementation period and discussed the initiation of several pharmacovigilance approaches, including a Yellow Card Biobank.

The EMA partnered with the Heads of Medicines Agencies, creating a task force to generate recommendations for how to benefit health using Big Data. Hans-Georg Eichler (EMA) presented the first steps in establishing funding to execute the plan laid out in the priority list generated by the task force. This will involve a cross-EU federated platform to permit queries on data across the different Member States.

North America
Sophie Sommerer (Marketed Health Products Directorate, Canada) described various changes as a result of Vanessa’s law:

  • Confidential business information can now be publicly released if there is a public health reason.
  • Hospitals must report all serious adverse drug reactions.
  • Biologics naming requires a non-proprietary active ingredient identification.

Gerald Dal Pan (FDA) explained that US adverse event reporting appears to be leveling off from its steady increase (as measured through the FDA Adverse Event Reporting System, FAERS). FAERS II is underway, which will allow receiving ICH E2B(R2) and (R3) safety reporting. FDA has a five-year strategic plan for updating Sentinel, FDA’s medical safety surveillance system, which includes incorporating more diversified data as well as adding advanced analytics to support better signal detection. Steven Anderson (FDA) presented a broader look at active surveillance at the FDA, which includes incorporating more data, more analytics, and pilot studies into the use of artificial intelligence to help automate reporting.

In-Depth Look at RMPs and REMS

Risk management is the concept of ensuring that the potential benefits of a medicine exceed the potential risks. Although this principle is shared across the US and the EU, actual implementation can vary considerably. In the EU, the EMA always requires sponsors to submit a Risk Management Plan (RMP) document for each drug being reviewed for approval. However, in the US, the FDA requires a similar document, a Risk Evaluation and Mitigation Strategies (REMS) plan, only if deemed necessary. Similar differences exist at the level of safety assessment.

Catherine Baldridge (Essential Pharmacovigilance) described factors that the FDA considers when determining if a REMS is required. Significantly, she also discussed one factor that the FDA does not consider: the capability of a company to actually produce a satisfactory REMS. Various options exist, from building an in-house REMS department to hiring a CRO to using external vendors, for a company to meet this requirement. Regardless of the method selected, a company requires an appropriate budget and effective leadership that can make the appropriate organizational changes needed to successfully implement a REMS program in a time crunch.

The case of thalidomide serves both as a practical example of the need for a risk management system and as a model of how a global strategy can be built effectively. In the 1950s, thalidomide was used to reduce morning sickness in pregnancy. It was later discovered that a single dose given 20-36 days after fertilization was sufficient to cause congenital malformations. Tragically, 12,000 infants would be born with birth defects before this drug was withdrawn from the market.

However, subsequent research into thalidomide found it effective for use in erythema nodosum leprosum (formerly known as leprosy) and multiple myeloma. Paul Sheehan (Celgene) described the core principles of Celgene’s risk management program to safely deliver thalidomide to patients while minimizing the evident risk. The company developed three different pregnancy prevention models that are selected and then tailored to the country-specific needs. The patient safety outcome of a million patients having been treated in 80 countries with zero children born with congenital abnormalities has served as evidence of the efficacy of a risk management plan.

Current Research on Mechanisms and Their Impact on Assessing Risks

Drug-Induced Liver Injury (DILI) is the most frequent reason for drug withdrawal, restriction, and modification of labeling. According to Hervé Le Louet (CIOMS), DILI is a growing problem that is responsible for more than ten percent of all cases of acute liver failure.

There are multiple challenges associated with addressing DILI. No tests are currently available to diagnose DILI directly. It remains an exclusion diagnosis, with an invasive liver biopsy being the gold standard for studying the pathophysiology. Even with a diagnosis, expert opinion during case review is the best assessment method, as no validated assessment scale is available. In addition, we currently lack predictive models to identify the risk of DILI pre-clinically. Research is underway to help discover and qualify new biomarkers as well as to identify potential genetic risk factors that may indicate DILI susceptibility.

Another promising therapy is the use of T-cells that have been genetically altered to express a chimeric antigen receptor – CAR-T cells. Peter Bross (FDA) presented a history of T-cell therapies starting with clinical studies in the 1990s and culminating in the first FDA approval of two CAR-T cell therapies in 2017. Almost all patients who receive CAR-T cell treatment develop a condition known as cytokine release syndrome (CRS)—so many that the presence of CRS is used to indicate that the therapy is working. Neurological toxicity is another associated outcome with a poorly understood mechanism. The severity of CAR-T cell toxicities led the FDA to require a REMS for both products prior to their approval. As new iterations of these cell-based therapies come down the pipeline, the benefit-risk equipoise will continue to remain a challenging pharmacovigilance issue.

Finally, Barbara Morollo (Corbus Pharmaceuticals) presented regulatory issues related to the endocannabinoid system (ECS). Various drugs either mimicking or manipulating the ECS have been developed and range from the pre-clinical to post-market stages. The US considers cannabis, a modulator of the ECS, a Schedule I controlled substance, which presents various regulatory challenges during clinical development due to the Federal Analogue Act. Practically, clinical investigations are required to maintain a separate licensure, secure drugs, maintain a chain of custody, and are subject to audits and inspections. The history of ECS drug development offers a look at the unique regulatory challenges existing with drug development, both pre-clinical and clinical, when using controlled substances.

Medication Errors

Medication errors are preventable events that can lead to medication misuse but do not necessarily result in an adverse event. Medication errors in the US have an estimated annual cost of nearly $21 billion and are responsible for an estimated 7,000 deaths, according to a study by the Network for Excellence in Health Innovation (NEHI). Christina Michalek (Institute for Safe Medication Practices) pointed out that medication errors have a significant impact on healthcare providers, in addition to affecting the primary victim.

Jo Wyeth (FDA) presented several approaches for medication error pharmacovigilance. Before approval, pre-market review can help identify issues before the medication even enters the market. Similarly, post-market changes must be considered in the context of the entire product lifecycle. For example, different dosages and formulations may benefit from different packaging. Finally, the entire reporting infrastructure must be evaluated to ensure that reports are completed accurately and that reporting itself is encouraged. Preventing medication errors through these approaches will require collaborative effort between patient safety organizations, standard-setting organizations, and regulators.

Real World Evidence (RWE)

In FDA’s definitions, Real World Data (RWD) are the data relating to patient health status and/or the delivery of health care routinely collected from a variety of sources, such as in an electronic health record. In contrast, Real World Evidence (RWE) is the clinical evidence regarding the usage and potential benefits or risks of a medical product derived from analysis of RWD.

RWD is generated throughout the drug development lifecycle, from discovery through lifecycle management. As Andrew Bate (GSK) put it, RWD is varied. Healthcare databases that contain RWD come from different countries and have different characteristics depending on how they were collected. Careful attention must be given to these factors when selecting sources of RWD for evidence generation.

The regulatory perspective of RWE has evolved. Since 1962, the FDA has been required to determine the effectiveness and safety of a drug based on substantial evidence collected in well-controlled randomized clinical trials. In 2016, Congress signed into law the 21st Century Cures Act, which mandated that the “FDA shall establish a program to evaluate the potential use of real world evidence.” As David Martin (FDA) pointed out, there is value in the regulatory use of RWD and RWE, including the inclusion of a more diverse patient experience compared to a traditional phase 3 clinical study. However, there remains a regulatory concern that the use of RWE may lead to a false conclusion about a drug’s effectiveness in the absence of the benefit of a randomized clinical trial.

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