ROCKY ROAD AHEAD FOR NEW FDA CHIEF CALIFF

Final Senate approval by a historically narrow 50-46 vote came only after the White House and Califf's supporters lobbied hard to gain sufficient support, a success that is very different from Califf's 89-4 approval back in 2016. Pressure to help control the high cost of prescription drugs will continue to drive FDA support for developing complex generic drugs and biosimilars. There is pressure to clarify rules governing e-cigarettes;a need to address serious health problems arising from contaminated food and seafood, including significant volumes of imported products;and the safety of cosmetic products, dietary supplements, sunscreens, and other non-prescription products raise additional complex issues.

PANDEMIC ALTERS POLICIES FOR DRUG DEVELOPMENT

The desperate need for new vaccines and therapies to tame the deadly COVID-19 virus required new policies and procedures for how biopharma companies select, test, and manufacture medical products-and revised regulatory practices for evaluating clinical data, manufacturing operations, and procedures for submitting and analyzing information. Vaccine experts at the Center for Biologics Evaluation and Research (CBER) worked overtime to clarify the size and diversity of efficacy trials and key analytical assessments needed to gain EUA status and later full approval, establishing standards and procedures that will shape research for health emergencies to come. Officials at FDA's Office of Regulatory Affairs (ORA) indicate that the agency will continue to utilize many of these strategies for streamlining oversight of manufacturing operations, even as on-site visits increase overseas and at home, leading to a more "hybrid" inspection process going forward.

FDA CAUGHT IN POLITICAL CROSSFIRE

FDA's oversight of medical devices and diagnostics has put it in the hot seat for shortages of critical products for protecting medical personnel and for providing fast and accurate public testing for COVID infection. The result is that the White House has delayed in selecting an FDA commissioner, even though federal rules require Woodcock to vacate her acting position by mid-November unless the administration nominates a new commissioner, permitting her to continue on during the Senate confirmation process. The approval decision by CDER officials was blasted by members of Congress, the medical community and even some patient groups, but justified by the reviewers as likely to provide some benefit to some patients who lacked any alternative treatment for this devastating disease.

INDUSTRY BACKS CLEAR FDA VACCINE STANDARDS

In spelling out the data expected for such authorization, agency officials emphasized the importance of fully vetting the safety and efficacy of any new coronovirus vaccine through a highly transparent process to boost public confidence in the ability of vaccines to save lives. Countering vaccine hesitancy Through the debate, officials in the Center for Biologics Evaluation and Research (CBER) emphasized that the EUA safety data requirement was already well known to vaccine manufacturers and that one aim was to assure manufacturers that FDA would hold all vaccine development programs to the same standards. Center for Biologics Evaluation and Research (CBER) Director Peter Marks further emphasized that the guidance sought to reassure the public that granting an EUA would not be a rushed decision on vaccine safety and efficacy to meet political goals, and that a vaccine EUA would require more data than for the more usual emergency authorizations for therapeutics and other medical products.

FDA'S 'GOLD STANDARD' CRITICAL FOR BIOPHARMA R&D

Last week, eight prominent biotech industry executives publicly emphasized the importance of rigorous clinical research and complete study data to support any authorization or approval of a new covid vaccine or treatment. Hahn raises concerns These statements aim to offset fears that fda might soften its approval standards due to pressure from the White House to make available a covid vaccine in October. Continuing predictions from the White House about a vaccine being available in two months, and instructions from the Centers for Disease Control and Prevention (CDC) that state public health departments should be prepared to distribute a vaccine by the end of October, heightened concerns that political pressure will lead to some kind of authorization of a new vaccine before the Nov. 3 election.

Early Vaccine Authorization Raises Ethical and Logistical Challenges for Trial Sponsors

The much-anticipated meeting of FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) last month addressed a number of critical issues related to testing and approval of vaccines to prevent COVID-19 infection, including policies and data requirements for determining that a pandemic vaccine can be considered safe and effective, particularly when based on more limited, early clinical trial data. While studies sponsored by AstraZeneca and Johnson & Johnson's Janssen unit resumed soon after the meeting, the study pauses were described by researchers as a sign that clinical trial safety systems were working as intended, as the analysts determined the adverse events were unrelated to the test vaccine candidates. The aim is to gain further information on vaccine efficacy and side effects, including rare adverse events and fuller comparisons among patient groups with differences in age, sex, comorbidities, and ethnic characteristics.

COVID ADVANCES CLINICAL TRIAL TRANSPARENCY

Growing public concerns about politics playing a role in vetting potential vaccines and therapies to combat the COVID-19 pandemic has prompted sponsors of leading clinical trials to make public their study protocols and statistical analysis plans. [...]AstraZeneca's timeframe for enrolling and assessing study participants was delayed by the need to address the report of a serious adverse event in its Phase III study. The disclosure of these usually confidential details on research endpoints, assessment timeframes, and study analysis plans aim to promote information sharing among vaccine developers, and also build public confidence.

Securing the Supply Chain

According to market research, the API market is expected to experience a compound annual growth rate of 6.7% in the forecast period of 2020-2027 (1). "The low-cost benefits of manufacturing APIs and drug products within Asia has helped to turbocharge the generic drug industry and expand global access to a range of lower-cost medication options," says Meudt. "The shift has been positive for patients, allowing consumers to benefit from lower cost drugs from US Food and Drug Administration (FDA) and European Union (EU) inspected current good manufacturing practice (cGMP) facilities while still maintaining quality, innovation, and allowing efficient drug development and commercialization routes," he says. "While manufacturing cost will always be important, pharmaceutical companies are increasingly selecting their long-term CMOs based upon other factors including security of quality and supply, regulatory track record, data control, and environmental sustainability.

The Pandemic as a Catalyst for Digital Pathology Adoption as an LDT

Whole-slide images (WSI) are the basis for the application of artificial intelligence/machine learning and other informatics methods to histological diagnosis and will further blur the line separating anatomic and clinical pathology. FDA classified WSI systems for primary diagnosis as class III (highest risk) medical devices until 2017. This discouraged anatomic pathology laboratories at risk-averse domestic institutions like mine from investing in these digital pathology (DP) platforms. In 2017, FDA downgraded WSI to class II (moderate risk) when they de-novo approved a system marketed by Philips. We were not interested in that system at my institution, but the downgrade caused us to reset our perception of the risk of validating a RUO system for primary diagnosis. Cost remained a barrier. In April 2020, FDA issued temporary guidance stating they would not enforce premarket approval of WSI systems to facilitate pathologists working remotely during the SARS-CoV-2 pandemic. The guidance included a statement that "laboratories and hospitals consider performing a validation study.” In January 2021, FDA proposed making the temporary non-enforcement guidance permanent. So, in a little more than three years, WSI for primary diagnosis had gone from class III to exempted from pre-market approval! This nicely aligned the approval framework for WSI with the approval framework for our conventional optical microscopes, which are statutorily exempted from approval, and further reset our perception of risk. In April 2021, FDA withdrew the proposal to make non-enforcement permanent, but the temporary non-enforcement guidance is still in effect at the time of writing. Amid all this FDA activity, the College of American Pathologists updated and reissued their consensus guidelines for validating WSI systems for diagnostic purposes in March 2021. The narrative mentions the FDA's recent approval of a few WSI systems and anticipates more, but the expert panel recommendations do not include any related to the approval status of systems. The reissue of this document reminded us that, as clinical laboratorians, we are capable of safely validating WSI as a laboratory-developed test and are supported in doing so by consensus guidelines from one of our leading professional organizations. In early 2021 we committed to funding a DP initiative to make WSI part of our routine histological process for 10% of our anatomic pathology cases. The initial capital investment is $1.5M. When realized, the microscope slides for designated pathology services will be transported directly from the cover slipper to a slide scanner and electronically distributed to pathologists using a clinical-grade image management system that we share with our radiology department. We made the decision to fund this in the context of the regulatory (decreased perception of risk), sociological (demand for remote telepathology), and technological (availability of scalable WSI systems) changes that occurred during the pandemic.

COVlD-19 vaccine Distribution: Preparing for the Unexpected

In December 2020, two shipments of the vaccine experienced temperature excursions in which product was actually kept at overly cold temperatures (3). Urgent need to protect data One problem that vaccine developers and regulatory agencies need to address is the urgent need to protect data, says Nigel Thorpe, technology director with Secure Age, which specializes in enterprise data encryption using a public key infrastructure platform. For operators on the plant floor, the efforts required are fraught with potential error, especially during shift changes, says Jim Evans, director of Verista, Inc.'s vision, connectivity, and automation division. Raw materials The speed with which vaccines have been developed and are being distributed pose important questions centred around variability. If we're having a raw materials shortage when the vaccines haven't even been scaled up, what will happen when they get full approval?" he asks.

Improving Agility Through Scalability

Miniaturized, modular, and continuous manufacturing processes will help speed scale-up, address supply chain complexity, and prevent shortages of important medications, Janet Woodcock, director of the United States Food and Drug Administration's (FDA's) Centre for Drug Evaluation and Research (CDER), noted during a meeting of the US National Academy of Sciences (NAS) in late February 2020. Describing the research at the NAS meeting (2), Rao said his team has conducted a demonstration project involving Neupogen (filgrastim) and is working with GE on development of remote bioreactor sensors to monitor analytes, oxygen, and carbon dioxide in smallscale systems in real time (2). [...]since research results were first published, he notes, robotics have been improved, and now include integrated online measurement systems using infrared (IR), FourierTransform IR, and high-pressure liquid chromatography and mass spectrometry so that key parameters can be measured in real-time, permitting online process monitoring as well as process optimization. Use of Raman and nuclear magnetic resonance (NMR) spectroscopy, refractive index, excipient identification, metabolite monitoring, and cell counts has now become routine, in both process development and manufacturing, says Christy.

Moving Clinical Operations Forward During Pandemic

In the short and long term, sponsors should think through: * Protocol modifications to incorporate remote patient and site assessments or other virtual elements. * Patient visit requirements and anticipated data collection challenges. * Effective resumption of activities when the pandemic situation improves. * Improvements to risk management planning.8 * Overall impact on clinical trial and clinical program timelines (including time to approval). [...]each passing day brings new information about the spread of COVID-19 globally. [...]to plan for the short and long term, sponsors should go back to the drawing board and reevaluate overall clinical study design, including patient eligibility, feasibility, enrollment, timelines, and budgets against the evolving global landscape. [...]alarming projections indicate that socialdistancing countermeasures may need to be in place well into 20219, which means that biopharmaceutical sponsors should make urgent decisions now to plan for continued clinical research in the coming months.

A comprehensive review on technological advances in alternate drug discovery process:Drug repurposing

The traditional de novo drug discovery is time consuming, costly and in some instances the drugs will fail to treat the disease which result in a huge loss to the organization. Drug repurposing is an alternative drug discovery process to overcome the limitations of the De novo drug discovery process. Ithelps for the identification of drugs to the rare diseases as well as in the pandemic situationwithin short span of time in a cost-effective way. The underlying principle of drug repurposing is that most of the drugs identified on a primary purpose have shown to treat other diseases also. One such example is Tocilizumab is primarily used for rheumatoid arthritis and it is repurposed to treat cancer and COVID-19. At present, nearly30% of the FDA approved drugs to treat various diseases are repurposed drugs. The drug repurposing is either drug-centric or disease centric and can be studied by using both experimental and in silico studies. The in silico repurpose drug discovery process is more efficient as it screens thousands of compounds from the diverse libraries within few days by various computational methods like Virtual screening, Docking, MD simulations,Machine Learning, Artificial Intelligence, Genome Wide Association Studies (GWAS), etc. with certain limitations.These limitationscan be addressed by effective integration of advanced technologies to identify a novel multi-purpose drug.Copyright © 2023, Association of Biotechnology and Pharmacy. All rights reserved.

Outsourcing's, Race Toward Novelty

According to Jeetendra Vaghjiani, senior director of clinical development and strategic marketing at Lonza, emerging biotech companies are reliant on contract development and manufacturing organizations (CDMOs) because of their development and manufacturing capacity, expertise, and flexibility. Because of the high attrition rate associated with drug development, the better your preclinical programme, the stronger the position you can establish in terms of programme design and patient identification (2). [...]because of the relative scarcity of approvals over the past decade, companies looking to capitalize on this new market are likely to require specialized knowledge to get through the approvals process.

Analysis: FDA's COVID-19 Accelerated Pathways

Current FDA programs to accelerate access In order to accelerate the product approval process, four regulatory programs currently exist to reduce development and review times for products that address unmet medical needs for the treatment of serious or life-threatening conditions. In May 2014, FDA issued a Final Guidance for Industry entitled, "Expedited Programs for Serious Conditions-Drugs and Biologics" which addresses fast track designation, breakthrough therapy designation, priority review designation and accelerated approval.3 In addition to this guidance document, under section 564 of the FD&C Act, 21 U.S.C. 360bbb3, in a situation where the Secretary of Health and Human Services (HHS) issues a declaration of emergency or threat justifying authorization of emergency use for a product caused by chemical, biological, radiological or nuclear (CBRN) agents, as well as an infectious disease, the Commissioner of the FDA may authorize an EUA of an unapproved product or an unapproved use of an approved product. In January 2017, the "Emergency Use Authorization of Medical Products and Related Authorities" guidance was finalized.4 Fast Track designation Section 112 of the Food and Drug Administration Modernization Act of 1997 (FDAMA), entitled "Expediting Study and Approval of Fast Track Drugs," mandates the facilitation of the development and processes to expedite review of therapeutics intended to treat serious or life-threatening conditions presenting with unmet medical needs. [...]a two-tiered system of review times, Standard Review and Priority Review was created.

US drug approvals rise in 2020 over previous year

Several medicines were approved as first treatments, including Gilead Sciences' Veklury (remdesivir) for patients with COVID-19 who require hospitalization (4);Amivas' artesunate for injection for severe malaria (5);Horizon Therapeutics Ireland DAC's Tepezza (teprotumumab-trbw), an antibody drug conjugate (ADC) for treating thyroid eye disease (6);and Ultragenyx Pharmaceutical's Dojolvi (triheptanoin) and Alnylam Pharmaceuticals' Oxlumo (lumasiran), both first treatments for metabolic disorders-Dojolvi for treating paediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (7) and Oxlumo (lumasiran) for treating the rare genetic disorder, primary hyperoxaluria type 1 (8). Blueprint Medicines Corporation) for treating unresectable or metastatic gastrointestinal stromal tumours harboring a platelet-derived growth factor receptor alpha exon 18 mutation (9);Koselugo (selumetinib, AstraZeneca Pharmaceuticals), for neurofibromatosis type 1 (10);Pemazyre (pemigatinib, Incyte Corporation), for certain types of previously treated, advanced bile duct cancer (cholangiocarcinoma) (11);Tabrecta (capmatinib, Novartis) for non-small cell lung cancer that has spread to other parts of the body and whose tumours have mutations that lead to MET exon 14 skipping (12);and Retevmo (selpercatinib, Loxo Oncology, a subsidiary of Eli Lilly and Company) for treating three types of tumours with alterations of the "rearranged during transfection" gene (13). Gilead, "U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma," Press Release, 24 July 2020.

EMA Marketing Authorization Recommendations Rise in 2020

[...]the committee recommended granting a conditional marketing authorization for Retsevmo (selpercatinib) for the treatment of cancers displaying a rearranged during transfection (RET) gene fusion, including RET-fusion positive non-small cell lung cancer, RET-fusion positive thyroid cancer, and RET-mutant medullary-thyroid cancer (1). The committee also recommended granting a marketing authorization under exceptional circumstances for Lumoxiti (moxetumomab pasudotox) for the treatment of relapsed or refractory hairy cell leukaemia (1). In January, the European Commission (EC) granted conditional marketing authorization to Moderna's COVID-19 vaccine (8), following a positive recommendation by EMA, based on positive Phase III clinical trial data that showed over 90% efficacy in participants at risk of severe COVID-19 and a 94% reduction in the number of symptomatic COVID-19 cases (9).

Four Key Trends for Identifying Regulator and Payer Evidence Needs in Oncology Drug Development

[...]patients have been restricted from accessing services, resulting in delayed diagnoses and potential disruptions to therapy. [...]there has been a new emphasis on accelerating the movement of treatment into the community setting. The overall economic forecast, and the forecast for drug budgets, have also been subdued due to the pandemic. 1.Benefit s of early advice in oncology strategy development Sponsors ca n be highly strategic: i n tlie cu rrent landscape by seeking regulatory and p ayep advice early in the drug developmeAt process. A number of recent Oncologic Drug Advisory Committee (ODAC) meetings have resulted in withdrawals of accelerated approval where confirmation of clinical benefit was not forthcoming or where confirmatory studies were not successful.

Early-Stage Considerations for the Manufacture and Delivery of Vaccines

Vials are versatile;in addition to liquids, they can be used to package lyophilized and cryogenic products, as well as those in powder form. If there are stability issues, reformulation will be required;this decision will be influenced by the nature of the vaccine, preferred shipping methods, and the container options. In-house manufacture may require investment in new capacity for a dedicated line for mass production of a single product or a flexible filling operation that can handle multiple products and different size vials. Depending on the future global needs for vaccinations, prefilled syringes may gain a significant market share.