Advancing pharmaceuticals and patient safety in Saudi Arabia: A 2030 vision initiative.

Low-quality medicines deliver sub-optimal clinical outcomes and waste precious health resources. It is important to ensure that public funds are spent on healthcare technologies that meet national regulatory bodies such as the Saudi Food and Drug Authority (SFDA), quality standards for safety, efficacy, and quality. Medicines quality is a complicated combination of pre-market regulatory specifications, appropriate sourcing of ingredients (active pharmaceutical ingredient (API), excipients, etc.), manufacturing processes, healthcare ecosystem communications, and regular and robust pharmacovigilance practices. A recent conference in Riyadh, sponsored by King Saud University, sought to discuss these issues and develop specific policy recommendations for the Saudi 2030 Vision plan. This and other efforts will require more and more creative educational programs for physicians, pharmacists, hospitals, and patients, and, most importantly evolving regulations on quality standards and oversight by Saudi health authorities.

21st century pharmacovigilance: efforts, roles, and responsibilities.

In an era when the number of expedited and conditional review pathways for newly available brand-name drugs and biosimilar medicines to treat serious and life-threatening diseases is increasing, defining pharmacovigilance has never been more crucial. 21st century pharmacovigilance is not merely about uncovering, reporting, and addressing adverse events associated with already approved and marketed agents, but can be described as the systematic monitoring of the process of pre-market review and post-market surveillance, which includes the use of medicines in everyday practice. Pharmacovigilance identifies previously unrecognised adverse events or changes in the patterns of these effects, the quality and adequacy of drug supply, and should ensure effective communication with the public, health-care professionals, and patients about the optimum safety and effective use of medicines. In this paper, the first in a Series of three about drug safety in oncology, we discuss evolving challenges in the purview, roles, and responsibilities of the US Food and Drug Administration and the European Medicines Agency with respect to pharmacovigilance efforts, with a special emphasis on oncology treatment.

Twenty-First Century Global ADR Management: A Need for Clarification, Redesign, and Coordinated Action.

Adverse drug reactions (ADRs) are estimated to be between the fourth and sixth most common cause of death worldwide, taking their place among other prevalent causes of mortality such as heart disease, cancer, and stroke. ADRs impact a broad range of populations across a wide variety of global geography and demographics, with significant mortality and morbidity burden in vulnerable groups such as older people, pediatric populations, and individuals in low-income settings. Too large a share of medicines risk management remains limited to signal detection in big ADR databases (USFDA, EMA, WHO, etc.) This resource allocation is antiquated and applied statistical signal detection methodologies have reached their limits of usefulness. In addition, existing databases are designed for short-term reactions, closely related to medication use and, thus, can only partially assess important broader consequences across geography, time, and clinical relevance. There is an urgent need change the dynamic. We need to identify (earlier and more regularly) many of the important but often overlooked or missed ADRs. Rather than assigning blame, we need to identify the root causes of the problem so they can be clearly addressed and fixed. The public health implications are profound-particularly as we recognize the importance of predicting and mitigating the next pandemic. Consequently, medicines risk management must be integrated within a broader global public health vision. To accomplish this, we need to develop the new tools and methodologies critical to assessing these public health imperatives.

Patient Contribution to the Development and Safe Use of Medicines During the Covid-19 Pandemic.

COVID-19 has catapulted the issue of the patient voice in healthcare and healthcare policy to the front of the global agenda. The world population has been affected with varying government-required risk mitigation measures including social distancing, national, regional and local "lock down" quarantines, and the wearing of masks along with diligent handwashing. Clearly, not all of these measures are possible in every country due to a lack of resources and healthcare infrastructure, and it will surely be patients who will suffer the most as a result. This issue must be dealt with responsibly on the local level by all countries and patients cooperating with and supporting overwhelmed healthcare systems and aiding the planned implementation of mitigation measures. If not, pockets of SARS-CoV-2 will remain in these regions with continuous suffering of their populations. This is critical as we still do not fully understand the clinical, pathological and epidemiological attributes of SARS-CoV-2; the longer it stays embedded and circulating, the possibility of mutation into a deadlier virus remains along with further waves of epidemics.

Impact of Real-World Data on Market Authorization, Reimbursement Decision & Price Negotiation.

Real-world data (RWD) and real-world evidence (RWE) appear now as complementary to traditional randomized controlled trials (RCT), that remain the gold standard of the evidence. This review aims to illustrate how health authorities in France, United States (USA) and United Kingdom (UK) can integrate RWD and RWE in market authorization discussions and in new pathways of price and reimbursement negotiations. We conducted a review from the literature, online investigations and interviews. RWD and RWE can be valuable in the context of market access, reimbursement decisions, price negotiation, pharmacovigilance and positive patient outcomes. While RWD could open new areas of innovative approaches and improve the efficiency of health systems, they have methodological limitations requiring further analysis to reach a sufficient level of proof. Moreover, misleading use of "RWD" and "RWE" terms is very frequent and even the definitions used by stakeholders (when they have one) are heterogenous. Because of the intrinsic characteristics of each product, the value given to these RWD may differ a lot, making them a useful tool more than an indispensable one. In sum, RWD and, more precisely, RWE have the potential to bring value to the health system at every step of the drug development process, from the discovery to the pharmacovigilance phase.

21st-Century Oncology Drug Safety via New-Age Regulatory Standards and Practices.

There is no such thing as a drug that is 100% safe or effective. Determining whether or not a new oncology treatment (or an additional indication for an existing medicine) should be approved by a regulatory licensing authority is, ultimately, as much regulatory science as public health art and nuance. There are many dynamic shifts in regulatory science (expedited review pathways, biomarker validation, use of real-world evidence, expanded off-label usage, etc) interpreted and expressed within the context of 21st-century oncology drug development, and these new tools and the learnings gleaned from them are helping to advance patient care. They are also helping us to carefully reconsider the levels of uncertainty we find in benefit-risk data and clinical calculations. New-Age Pharmacovigilance can be a tool in product development, regulatory review, postmarketing surveillance and enhanced clinical outcomes.

FDA and the critical path to twenty-first-century medicine.

One of the most pressing issues that confronts the Food and Drug Administration (FDA) is learning how to better address and assist in medical product development. FDA needs to prepare today so the agency can efficiently evaluate the technologies of tomorrow. Clearly, this is an area that impacts not only health care consumers but also our economies and financial markets. If the FDA can be a more aggressive part of the solution, they can help not only ease some of the pressures that are driving up health care costs but also help all of us to maximize the value of medical innovations. The high cost of research and development is forcing many companies to make the short-term business decision to focus product development on those molecules that have a much higher potential to recoup expenditures. Unfortunately, this trumps attempts to develop potentially risky but breakthrough products for diseases affecting smaller populations, the orphan drugs. FDA's critical path initiative will enable innovative growth companies to better and more efficiently attack the steep hurdles facing them, allowing them to compete more effectively against the bigger, better-funded players in the market on a more level playing field. That means a real change in the risk/benefit equation for both the emerging growth companies and the public health.

From the Valley of Death to the Crossroads of Opportunity: A Discussion of Evolving Benefit/Risk Evaluation Standards.

A series of recent US Food and Drug Administration (FDA) approvals (such as Sarepta's Exondys 51, Merck's Keytruda, and Portola's Bevyxxa) has generated significant interest within the drug development ecosystem. Facilitated regulatory pathways aimed toward expediting medicines to patients suffering from serious and life-threatening conditions are a good thing, even if it raises curiosity and introduces some degree of uncertainty. Over the last 20 years, two key words in drug development have been speed and innovation. Going forward, the patient voice, data quality, and evidence generation must be added to that list. There is a raging debate over the level of evidence expected to first introduce a treatment to patients. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in the regulatory framework is happening in front of our eyes. How are these shifts in regulatory science interpreted within the context of 21st-century drug development-and how can these learnings help advance patient care while placing into context the expected uncertainty we find in benefit-risk data?

Advancing Drug Safety Through Prospective Pharmacovigilance.

Much has changed in a relatively short period of time. There is a raging debate over the level of evidence expected to first introduce a treatment to patients based on smaller, more adaptive data sets. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end-point modification driven by patient-focused drug development and use of real-world evidence. The transition in both the review and postmarketing regulatory framework is happening in front of our eyes in real time. To improve the ability of patients to receive high-quality, safe, effective, and timely care, better information via pharmacovigilance must be a priority as the world's many regulatory systems build the capacity to harness electronic health information to improve health, care quality, and safety. Globally, the widely variable ability of nations to build reliable regulatory systems (from precise review to robust pharmacovigilance) is a dangerous source of health care inequality. Developing validated tools and techniques for "predictive pharmacovigilance" will assist all health systems in better understanding the risks and benefits of the medicines they regulate by understanding what should be happening once a new medicine moves from risk-benefit regulatory efficacy to real-world risk-effectiveness. This will be of particular utility for smaller regulatory agencies with fewer resources. By comparing preapproval predictive pharmacovigilance data, developing regulatory authorities will be able to better understand the potential gap between what was predicted and what was actually measured (via more traditional pharmacovigilance methodologies). Predictive pharmacovigilance recognizes the value of understanding the imperfect reporting of real-world clinical use and that the absence of reporting is, in itself, an important postmarketing signal.

Using Off-Label Communications to Responsibly Advance the Public Health.

The debate over off-label communications doesn't begin or end with the Caronia or Amarin decisions. It's a continuing dialogue between manufacturers and the FDA, between doctors and patients, between doctors and academics, between lawyers and judges, and between advocates on all sides. And the red thread that ties these conversations together is responsible off-label communications. Not sales strategies. Not Direct-to-Consumer (DTC) advertising and marketing tactics. Not managed market negotiations-the responsible sharing of truthful and accurate information via nonregulated speech. Off-label communications, properly done, advances precision medicine, delivering speedier positive patient outcomes and reducing costs to our health care system. Off-label communications provides patients with more options for effective medicines.

Implications of CRISPR-Based Germline Engineering for Cancer Survivors.

Cancer survivors can carry germline mutations that will be transmitted to their progeny. Today, many of these mutations have been identified and can be tracked. With the recent development of genome-editing technologies and CRISPR (clustered regularly interspaced short palindromic repeats), the possibility of genetically modifying the human germline-gametes and embryos-has never been closer. This perspective has sparked a controversy within the scientific community with reactions ranging from calls for a ban on germline modification to cautious approval of further research. This Editorial analyzes the possible adoption of CRISPR-based germline engineering to prevent the spread of cancer predispositions in the human population. We discuss whether the genomic edition of human sperm and eggs would contribute to rectifying or altering the heritable genome. We anticipate the emergence of a new form of liberal eugenics fueled by a logic of offer and demand from stakeholders such as cancer survivors and their relatives and offspring, but also from fertility clinics, biotech firms, insurers, and clinicians. From a regulatory perspective, validating the clinical safety and utility of CRISPR-based germline engineering is an essential step. However, with time, gradually perfecting the technology and assessing the economic benefits for stakeholders could soften society's resistance and align opinions in support of genomic decontamination of human germlines. This progressive shift would be justified in the name of cancer prevention as well as a moral obligation to facilitate the conception of cancer-free children at a cost that is acceptable to individuals and health systems.