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Dec 2, 2019

Would FDA support these approaches: Flipped Clinical Trials and One Indication, One Standardized Protocol, Multiple IMPs?
On 7 November 2019 the FDA held a public meeting on Promoting Effective Drug Development Programs: Opportunities and Priorities for FDA's Office of New Drugs

The purpose of this public meeting is to solicit from external stakeholders specific, actionable policy suggestions that could be implemented in the near-term by the review staff of the Office of New Drugs (OND) in the Center for Drug Evaluation and Research (CDER) to promote effective drug development programs without compromising our regulatory standards for assessment of safety and effectiveness. Dr. Peter Schiemann, Managing Partner at Widler & Schiemann LTD, presented the cases of Flipped Clinical Trials and One Indication, One Standardized Protocol, Multiple IMPs Sharing Data from Standard Therapies.

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Report from the Commission to the European Parliament and the Council on the National and European Medicines Agency Experience Regarding the List of Medicines for Human Use Subject to Additional Monitoring
On 15 November 2019 the European Commission published the report concerning the experience gained regarding Additional Monitoring

Regulation (EC) No 726/2004 and Directive 2001/83/EC provide the EU legal framework for pharmacovigilance for medicinal products for human use. The provisions on pharmacovigilance were amended in 2010 and 2012. As a result of the changes the tasks and responsibilities for all parties were outlined within a proactive and proportionate risk management system. The link between safety assessments and regulatory action, along with transparency, communication and patient involvement were strengthened. This report concerns the experience gained regarding ʻadditional monitoringʼ, a specific aspect of pharmacovigilance activities which was introduced through the revision of the legislation.

The Member States and the European Medicines Agency (EMA) collected information on the experience of the implementation of the additional monitoring of medicines through:

a. A survey to estimate patient and healthcare professional (HCP) awareness of the black symbol and the additional monitoring concept.

b. EMA’s experience with the use of the additional monitoring list and a study on whether the inclusion of products on the list had an effect on reporting of their ADRs.

c. A survey to understand Member States’ experience with additional monitoring.

A joint report of the Heads of Medicines Agencies (HMA) and EMA based on the above surveys and analysis forms the main basis of this report.

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Procedural advice for orphan medicinal product designation
On 19 November 2019 the EMA updated this guidance for sponsors.

In examining an application for orphan medicinal product designation, the COMP will focus on determining whether the sponsor has established that the designation criteria are met, i.e.:

  • the life-threatening or debilitating nature of the condition;
  • the medical plausibility of the proposed orphan indication;
  • that the prevalence of the condition in the European Union is not more than five in 10,000 or that it is unlikely that marketing the medicinal product in the European Union, without incentives, would generate sufficient return to justify the necessary investment;
  • that no satisfactory method of diagnosis prevention or treatment exists, or if such a method exists, that the medicinal product will be of significant benefit to those affected by the condition.

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Transdermal and Topical Delivery Systems - Product Development and Quality Considerations
On 20 November 2019 the FDA announced the availability of the draft guidance for industry. Comments may be submitted by 19 February 2020.

This guidance provides recommendations to applicants and manufacturers of transdermal and topical delivery systems (TDS) regarding the pharmaceutical development and quality information to include in new drug applications (NDAs) and abbreviated new drug applications (ANDAs). Specifically, the guidance discusses FDA’s current thinking on product design and pharmaceutical development, manufacturing process and control, and finished product control. It also addresses special considerations for areas where quality is closely tied to product performance and potential safety issues, such as adhesion failure and the impact of applied heat on drug delivery.

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Certificates of Confidentiality
On 22 November 2019 the FDA announced the availability of the draft guidance for Sponsors, Sponsor-Investigators, Researchers, Industry, and FDA Staff. Comments may be submitted by 08 January 2020.

This draft guidance describes FDA implementation of the revised provisions applicable to the request for, and issuance of, a Certificate of Confidentiality (CoC). The 21st Century Cures Act (Cures Act) (Public Law 114-255) amended the Public Health Service Act (PHS Act), section 301(d) (42 U.S.C. 241(d)) relating to the issuance of CoCs. A CoC is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. Historically, a CoC generally protected a researcher from being compelled to disclose identifiable and sensitive information about the research participant, created or compiled for purposes of the human subject research. As amended, the statute broadened the protections by affirmatively prohibiting holders of CoCs from disclosing such information unless a specific exception applies.

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Clinical Immunogenicity Considerations for Biosimilar and Interchangeable Insulin Products
On 25 November 2019 the FDA announced the availability of the draft guidance for comments by 27 January 2020.

The purpose of this guidance is to provide recommendations to applicants regarding whether and when comparative clinical immunogenicity studies may be needed to support licensure of proposed biosimilar and interchangeable recombinant human insulins, recombinant human insulin mix products, and recombinant insulin analog products that are intended for the treatment of patients with Type 1 or Type 2 diabetes mellitus (collectively described as “insulin products”). The recommendations in this guidance are applicable only to proposed biosimilar and interchangeable insulin products seeking licensure under section 351(k) of the Public Health Service Act (PHS Act) in biologics license applications (BLAs).

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Adaptive Designs for Clinical Trials of Drugs and Biologics
On 29 November 2019 the FDA announced the final guidance for industry. Adaptive designs for clinical trials allow for prospectively planned modifications to one or more aspects of the design based on accumulating data from subjects in the trial. They are intended to support the effectiveness and safety of drugs.

This document provides guidance to sponsors and applicants submitting investigational new drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of adaptive designs for clinical trials to provide evidence of the effectiveness and safety of a drug or biologic. The guidance describes important principles for designing, conducting, and reporting the results from an adaptive clinical trial. The guidance also advises sponsors on the types of information to submit to facilitate FDA evaluation of clinical trials with adaptive designs, including Bayesian adaptive and complex trials that rely on computer simulations for their design.

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How to handle remote monitoring?
EFGCP audit working party discussed the questions regarding to the remote monitoring.

Dr. Beat Widler, Managing Partner at Widler & Schiemann LTD, provided his insights on some questions regarding to the remote monitoring. First, especially BfArM (Bundesinstitut für Arzneilmittel und Medizinprodukte, German Authority) inspectors do not approve such approach, i.e., monitoring and Source Data Verification (SDV) in this context done remotely with the site staff verifying the source data. Such approach blurs the roles and responsibilities between clinical trial center and sponsor (monitor). Site staff should focus on running the trial and manage / support the patients, while the monitor verifies that the protocol is properly implemented and data in the Case Report Form (CRF) are ALCOAC (Attributable, Legible, Contemporaneous, Original, Accurate, Complete).

Q: Is it OK with webex together with the Study Coordinator to confirm certain data points remote before an interim analysis?

A: If it’s an isolated spot-check to confirm some few data points, e.g., data that raised a flag upon centralized data review - then it’s OK.

Q: How do you protect patient integrity?

A: Resolving a few queries over the phone while the monitor queries some data points and the coordinator checking the medical records and then making the required changes in the CRF / completing a query is OK. But if you want to replace monitors visit with off-line sessions where the coordinator in fact is performing the monitor’s task, some inspectors may not consider this to be an acceptable practice.

Q: Could it be other staff from the sponsor viewing the medical records?

A: BfArM in a public event was adamant that even sharing of images of medical records with the sponsor is a violation of data protection as the sponsor could take screen shots and the clinical trial center has no way to ensure this doesn’t happen (and trusting this doesn’t happen is not good enough)

Q: Do you expect the CRA to re-confirm these data-points afterwards during normal monitoring at site?

A: In the scenario - i.e., talking about the verification of some few data points over the phone – there is no need for a reconfirmation by the monitor.

Centralized monitoring has little if nothing to do with remote data verification or remove SDV. Centralized monitoring means a holistic approach of monitoring your clinical data by means of prospectively defined KPIs and KRIs and associated Quality Tolerance Limits (QTLs) plus applying smart statistical tools to identify "data outlier hotspots”. The Tufts paper - to which TransCelerate makes reference - makes clear statements about the value of SDV: SDV doesn’t get any more valuable when it’s done remotely rather than on site. On the contrary, with on-site SDV one waste time of 1 person with remote SDV the same time but of TWO! people.


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