【讨论】New FDA Guideline on Size, Shape and Physical Attributes of Generics

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At the end of 2013, the FDA published a guideline draft entitled "Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules". The Agency saw a need for regulation because of the fact that the dosage forms of generics - particularly tablets and capsules - may considerably differ in shape and size from reference listed drugs (RLD) despite of equivalent pharmacological parameters. The FDA is concerned that this could affect patient compliance and acceptability of medication regimens and thus could pose a risk to patient safety. This mainly applies to patients suffering from dysphagia. For them swallowing a tablet or a capsule of a larger size may be almost impossible.
This guidance addresses companies who want to submit a marketing authorisation dossier in the USA either for a generic medicinal product or for an additional strength of an already authorised generic. The Guidance doesn't apply to already marketed generics and oral dosage forms other than tablets and capsules.
The Guidance formulates requirements with regard to the dimensions, volume measurements and further physical attributes of tablets and capsules which have to be taken into consideration by the generics manufacturers. For example, the largest dimension shouldn't basically exceed 22 mm. For smaller dimensions or volumes of the RLD, the generic dosage form may be larger only within specified limits. If the physical attributes defined in this Guidance are exceeded, the applicant should contact the Agency before submitting the authorisation dossier. Studies in the development phase with dosage forms which have physical attributes outside the limits set have to be described in CTD module 3, chapter 3.2.P.2, "Pharmaceutical Development" or 3.2.P.5.6, "Justification of Specifications".
The provisions on the characteristics of generic oral dosage forms are summarised in the chapter "Recommendations" of the Guidance. Like every FDA Guidance for Industry, the "recommendations" described should be considered as binding as the Agency's reviewers definitely use these regulations. Generics manufacturers who want to get an authorisation for the US-American market should thus accurately align to this Guidance.

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The Center for Devices and Radiological Health (CDRH), responsible for medical devices at the FDA, publishes new guidelines and programmes on a regular basis. Following you will find a short and selected overview of new, modified, or updated guidelines and programmes.
The guideline "Design considerations for pivotal clinical investigations for medical devices" is new. With 57 pages this guideline is very extensive. It is supposed to provide assistance in the planning of clinical trials for medical devices which are subject to a "Premarket Submission". This "Premarket submission" is kind of an approval process for medical devices, and especially with the risk class III (medical devices with high risk). The guideline not only addresses the industry but also FDA staff processing "Premarket Submissions". Anyone looking for information in addition to the guideline may also take a look at thepresentation from the CDRH Department of Biostatistics Director on this topic.
Also new is a draft of the guidance document with the title Medical Device Development Tools. This document introduces a voluntary process for the qualification of tools for the development of medical devices. Through the use of these tools, the FDA hopes for a faster evaluation of innovative medical devices in the approval process. In this respect, the draft also addresses the industry as well as FDA staff.
To improve the quality of medical devices, the FDA started the programme "Case for Quality" in 2011. Here you can find a current evaluation of the programme. In connection with "Case for Quality" the FDA also started a Voluntary Compliance Improvement Program (VCIP) pilot case for quality. The programme is designed to provide an alternative to the classical FDA supervision.
The issue of identification of medical devices (UDI) has a high priority at the FDA. We have already reported. Those who want more information now have the chance to look at two presentations on the CDRH website - on the Introduction of UDI and on the control itself.
Furthermore, other changes were made in a list of standards which are of regulatory relevance to medical devices. Under the title "modifications to the list of recognized standards, recognition list number: 033" these changes are listed.
The "Guidance for industry and food and drug administration staff annual reports for approved Premarket approval applications (PMA)" was finalised. It provides assistance in the preparation of annual reports for medical devices under a Premarket Approval Application. With 12 pages this guideline is not very extensive, and 3 pages list the content of an annual report.
Also finalised was the question and answer paper: Questions and Answers about eMDR - Electronic Medical Device Reporting. The 13 pages document supplies information with regard to electronically written reports about adverse events with medical devices.
The now finalised guideline "Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meeting with Food and Drug Administration Staff" addresses applicants for clinical trials and for approvals of medical devices. The 57 pages guideline also references applications regarding clinical trials with medicinal products (IND) and approvals of biological medicinal products (BLA).
The draft of the guideline "Humanitarian Device Exemption (HDE): Questions and Answers Draft Guidance for HDE Holders, Institutional Review Boards, Clinical Investigators, and Food and Drug Administration Staff " comprises special questions with regard to the registration of medical devices which only concerns a very small circle of patients (< 4000 affected per year in the United States).

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At the end of March, the FDA announced in the Federal Register that changes to 21 CFR 860 (Medical Device Classification Procedures) were planned. Chapter 860 is divided into 3 subchapters (General, Classification, Reclassification). Based on risks, the classification includes 3 classes (class I, II, III). Class III comprises the highest risks with regard to safety and efficacy of a medical device.
According to its risk class, a medical device will be placed under different regulatory requirements. Class I products "only" have to comply with general controls which are laid down in the Food, Drug and Cosmetic Act (FD&C Act). Surgical instruments are for example typical class I products. Class II products are subject to special controls in addition to the general ones (i.e. strengthened requirements on market monitoring) Examples of class II products are infusion pumps and acupuncture needles. Class III products underlie a "premarket approval" procedure which is comparable to a marketing authorisation for Medicinal Products/Drugs. Class III products include for example pacemakers and HIV test kits. A standalone database is available for the classification of medical devices.
The changes to 21 CFR 860 are required to be able to fulfil the necessary provisions from the "Food and Drug Administration Safety and
Innovation Act (FDASIA)". Part of this legislation also aims to enhance public health protection and encourage innovations in order to faster access of products to the market. In parallel, classification into the lowest class shall also be adapted to the legal requirements.
The changes planned are very extensive and concern almost every subparagraph of 21 CFR 860. New sections should be added like 21 CFR 860.90--Consultation with Panels, and 21 CFR 860.133--Procedures When the Commissioner Initiates a Proceeding to Require Premarket Approval under 515(b) of the FD&C Act.
Conclusion: The changes planned to 21 CFR 860 (Medical Device Classification Procedures) are significantly comprehensive. The proposals can be commented until 23 June 2014.
Please click here to access the announcement about the changes to 21 CFR 860 and the respective text.

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The FDA has published an overview over the evolution of medical device recalls between the fiscal years 2003 and 2012. In 2010, the FDA started an initiative to improve recall processes in order to enhance public health. The report should thus help to increase understanding between the FDA and the industry in order to better protect the population against unsafe or limited useful medical devices.
Please find below some of the significant report outcomes:
Over the 10-year period, the number of annual recalls has increased by 97%.
Class I recalls have also increased over that period (Class I recalls have high priority as they are likely to lead to health hazards) They mainly concerned ventilators, infusion pumps and external defibrillators.
In the last 3 years, the Center for Devices and Radiological Health (CDRH) also reduced the average times for the classification of a recall (Class I, II, or III, depending on the criticality): Class I recalls by 9 days and Class II by 26 days.
The principal causes for recalls are related to device design, software, and non-conforming material or component issues. If the CDRH and the industry would address these problems jointly, they may be able to prevent as many as 400 recalls annually.
For the CDRH, the report is part of a larger initiative to enhance public health. In this respect, the CDRH has taken different measures to improve the recall programme; among other things a systematic analysis of recall information, the establishment of a "Recall Process Improvement team", the integration of improved methods for reporting recall information to the stakeholders and improved internal processes to incorporate recall root causes in premarket reviews.
More information can be found in the Medical Device Recall Report.

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At the end of 2013, the FDA released the final version of the Guidance for Industry and FDA-Staff on "Investigation Device Exemptions (IDEs) for Early Feasibility Medical Devices Clinical Studies Including Certain First in Human (FIH) Studies". This is the final version of a draft from November 2011.
In total, the document contains 40 pages: 28 pages are actual Guidance text, and the remaining 12 pages are divided into 4 appendices. The Guidance explicitly addresses FDA employees, clinicians, "innovators", and industry using IDEs. The focus is primarily on studies with significant risk devices (according to 21 CFR 812 (m)) including - for example - certain implants. It is expressly referred to a benefit-risk analysis and protection measures for the patient.
Essential elements for the application and authorisation of an IDE are among other things a development strategy for medical devices as basis for the data to be collected in early feasibility studies. Reports of prior investigations, clinical plant and risk reduction strategies are further elements.
The 4 appendices of this guidance are particularly interesting:
1. Recommended topics for a Pre-Sub for an early feasibility study IDE
2. Device evaluation strategy example
3. Supplemental guidance for the preparation of an early feasibility study informed consent document
4. Device iteration example
Section 6.3 of the Guidance text already presents a table for an appropriate strategy (see also Annex 2).
The complete Guidance can be found here. Moreover, if you are interested in a CDRH presentation on the topic, you can find detailed information here.
Conclusion: The 40-page Guidance is very extensive and provides - fortunately - concrete support thanks to (hypothetical) practical examples in the form of 4 annexes.