Understanding the FDA’s GMP Expectations for Phase I and First-in-Man Clinical Trials

The establishment of the initial safety of a drug is the primary reason for which early clinical trials are conducted. Phase I of drug development consists of:

o  Research and drug discovery

o  Preclinical development, of which initial IND, or first in humans (also called first in man), is part

o  Clinical development, which consists of Phase I, Phase 2 and Phase 3 clinical pharmacology studies

Phase I studies are designed mainly for investigating the following qualities of an investigational drug in humans:

o  The extent to which it is safe and tolerable: (if possible, identify its Maximum Tolerated Dose (MTD)

o  Pharmacokinetics

o  Pharmacodynamics of an investigational drug in humans.

The ultimate goal of these Phase I and later studies is to ensure that the right drug is given to the right patient in the right dose, at the right time. These clinical studies are carried out to determine which dose or dosing regimen of the target drug achieves all its objectives for all the populations groups for which it is being developed.

Rationale for a small sample

Generally, these studies are carried out on a small sample of subjects of normal health. These early clinical trials normally use lower doses of the drug product. On account of this, the organization or laboratory carrying out these early stage clinical studies uses only small amounts of investigational material.

This is because of two reasons: The small sample is chosen in such a fashion that it is a representation of the whole study in relation to various parameters, and two, choosing a small sample substantially reduces the costs associated with a largescale study. It also reduces the regulatory burden during these early stages. Keeping in mind these factors, the FDA has established guidelines by which early stage investigational products can be allowed to be manufactured under less stringent GMPs.

Not meeting regulatory requirements makes the exercise futile

Without an understanding of the FDA’s guidelines for these GMPs, the whole exercise of early or Phase I studies becomes wasteful and meaningless. All along, the FDA’s guidelines have to be consistently and accurately adhered to in order to meet compliance requirements, without which the clinical trial and its results do not get approved.

What are the steps that a clinical or pharmaceutical organization need to take in order to ensure that these GMPs for Phase I clinical trials are being met? All the aspects of this topic will be covered in depth over two days of intense learning that will be imparted at a seminar from GlobalCompliancePanel, a leading provider of professional trainings for the areas of regulatory compliance.

Peggy Berry, the President and CEO at Synergy Consulting where she provides consulting services to companies in all aspects of drug development, will be the Director of this seminar. All that is needed to gain from the rich wealth of Peggy’s experience is to register for this seminar by logging on to Good Manufacturing Practices . This course has been pre-approved by RAPS as eligible for up to 12 credits towards a participant’s RAC recertification upon full completion.

A complete explanation of the FDA’s GMP requirements

This seminar is being organized to help participants gain an understanding of the requirements for advancing drugs from research into early clinical development and the minimum FDA requirements for Phase I GMPs. She will help them learn practical applications for implementing Phase I manufacturing strategies to meet FDA requirements.

Towards this end, Peggy will discuss these topics to lay the foundation and basis for advancing drugs into clinical development from research and providing required information to the FDA regarding these products on Day 1:

o  Moving a Product out of R&D

o  CMC Requirements for an IND Study

o  Good Manufacturing Practices: Basics for Beginners

o  Raw Material Management

Taking off from these topics, Peggy will focus on the topics relating to the requirements for early stage products of different types and for vendor selection and management on Day 2, which include:

o  GMPs for Phase I IND products

o  GMPs for Combination Products and 505(b)(2) Products

o  Process Validation for Early Stage GMP

o  Outsourcing Early Stage Manufacturing.

The ingredients of a truly effective internal audit program

 

AFirst Sliden internal audit program of an organization’s Quality Management Systems is a core requirement from both the ISO and the FDA. At its barest, an internal audit system can be understood to be an assessment or inspection of an organization’s Quality System. Audits are a very beneficial and positive tool for continually ensuring that an organization’s internal management systems are up to the mark and keep meeting regulatory requirements on a consistent basis.

An internal audit program is the most effective and useful tool in helping an organization discover its loopholes and deficiencies in the Quality System, which is absolutely essential to help it pass regulatory hurdles. The purposes of an internal audit, as set out by ISO 9001, which describes Quality Management Systems audits, are to ensure that:

  • The Quality Systems of the organization comply with the requirements of ISO 9001 and its latest versions
  • They show compliance with the requirements of other regulatory bodies such as the FDA
  • They comply with the quality requirements the organization has
  • The organization makes effective implementation and maintenance of the QMS.

ISO 9001 does not require the internal audit procedure to be fully documented. An organization has to only, to use the ISO’s own words, “maintain an audit program” and retain the documents relating to the audit and its results and information contained in them.

Multifold benefits of auditing

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Auditing, both external and internal, bring many benefits. Besides meeting the purposes as set out by ISO 9001 and others such as the FDA; auditing helps organizations:

  • Identify the areas in which they need to make improvements
  • Apply best practice relevant to the particular industry
  • Take preventive actions that could nip potential problems in the bud
  • Ensure greater customer satisfaction.

Compliance with audit requirements is considered drudgery

Despite the noble intentions behind internal and external audits; three fourths of organizations consider audits as being very cumbersome, unpleasant and baneful. Most of them carry out audits with no conviction. They carry them out only because they have no other choice. Most businesses fail to see the value behind the efforts needed for carrying out audits that meet regulatory requirements.

Carrying out audits without any sense of purpose results in more drudgery and unpleasantness. The result of carrying out audits for the sake of it, rather than with purpose is there to see: More Warning Letters, 483’s, penalties and other actions such as even Consent Decree, from the FDA.

Learn to carry out effective audits more willingly and effectively

The ways by which organizations can overcome the mental barrier to carrying out audits and put in place a well-planned, compliant audit program that reduces the risk of noncompliance will be the teaching a two-day seminar from GlobalCompliancePanel, a leading provider of professional trainings for the regulated industries, will be offering.

Susanne Manz, Quality and Compliance Expert/Auditor for Medical Devices, Manz Consulting, Inc., who is an accomplished leader in the medical device industry with emphasis on quality, compliance, and Six Sigma, will be the Director of this seminar. To enroll for this webinar and gain complete understanding of the means for planning and implementing a Quality Systems audit that meets regulatory requirements,

Please register by logging on to http://www.globalcompliancepanel.com/control/globalseminars/~product_id=900854SEMINAR?wordpress_SEO. This seminar has been pre-approved by RAPS as eligible for up to 12 credits towards a participant’s RAC recertification upon full completion.

A complete understanding of the rationale and ways of carrying out compliant audits

This seminar will be highly useful in helping audit professionals in organizations devise an effective audit program with is compliant. It will put participants on the path to a thorough quality audit program that meets regulatory requirements. Such a well devised quality audit program is a powerful tool in helping organizations to understand, reduce and communicate risks relating to quality and compliance.

Susanne will open the participants’ minds to continuous improvement, which starts with the awareness of issues and opportunities. The absence of an effective audit program deprives management of an understanding of the issues within their Quality System. As a result, management is oblivious to the lacunae in the Quality System and the risk bring for the organization. Such a situation denies the management the opportunity to assess the impact a faulty Quality Management System audit has on product quality and the risk it poses to the customer. Susanne will draw participants’ attention and focus on the red-flags and explain to them the ways by which they can reduce compliance and quality risk.

This seminar will consist primarily of lectures, interactive discussions and practical exercises. Susanne will equip the participants with the tools and techniques they need for ensuring compliance of their Quality Systems audits. They will walk away with an understanding of the key concepts and their practices, along with the ways of implementing them and use them as reference for future use

 

FDA requirements on data integrity and its implementation

The phrase “data integrity” seems to be everywhere. It is used in a number of places and situations, and the FDA has its own definition of the term. At its plainest, data integrity is defined as the assurance that data is complete, consistent and accurate. FDA requires this data to be attributable, legible, contemporaneously recorded, to be an original or a true copy, and to be accurate. This criterion is embodied in the acronym ALCOA.

Is just an understanding of this definition sufficient? In order to understand data integrity from the computerized systems point of view; one has to apply 21 CFR Part 11 and Annex 11 to data. Its implementation is considered difficult for a number of reasons. To apply data integrity to computer systems, one needs to understand the concept of data integrity.

Understanding is necessary in view of the FDA’s stepped up inspections

It is only this basic understanding that will help to determine what needs to be done to meet national and global data integrity requirements. This is all the more important in view of the fact that regulatory agencies such as the FDA have accelerated inspections related to data integrity, as a result of which there has been a big rise in the number of citations relating to data integrity.

When it comes to data integrity for computerized systems, the requirements set out in 21 CFR Part 11 and Annex 11 need to be kept in mind from the following perspectives:

o  The background to and the way in which 21 CFR Part 11 and Annex 11 have evolved and why they are being talked about all over again

o  An understanding of the full overview of Part 11 and Annex 11 and their key requirements

o  Clear understanding of how the use of Risk Based Assessment will not only achieve data integrity and compliance but also bring down work considerably

o  The FDA’s and other regulatory authorities’ method of inspecting computerized systems for data integrity.

A complete two-day exploration of data integrity from the FDA’s perspective

It is to familiarize IT professionals and professionals who work on data integrity that GlobalCompliancePanel, a leading provider of professional trainings for the areas of regulatory compliance will be organizing a two-day seminar.

The Director of this seminar is Angela Bazigos, who is CEO of Touchstone Technologies Silicon Valley. Angela brings over 40 years in the healthcare and life sciences industries. To gain the benefit of Angela’s experience in the industry and to discover ways of ensuring data integrity in the computer systems of a number of healthcare and life sciences disciplines, please register for this seminar by visiting http://www.globalcompliancepanel.com/control/globalseminars/~product_id=900946SEMINAR?wordpress_SEO . This course has been pre-approved by RAPS as eligible for up to 12 credits towards a participant’s RAC recertification upon full completion.

Practical understanding of data integrity

This seminar is very hands-on and is meant to offer guidance on how to ensure data integrity in highly regulated industries. It is of relevance and importance to both beginners and experienced professionals alike. She will offer a completely detailed experience of validation and 21 CFR Part 11 compliance that a computer system needs to have.

One of the major takeaways of this seminar is the templates Angela will give to participants, which will help them build a full package for meeting data integrity for computerized systems. She will also detail the activities associated with Computer Systems Validation, exploring areas such as:

o  What is Data Integrity and how is it implemented

o  How to use Risk Based Assessments to reduce work while still achieving Data Integrity and Compliance?

o  Data Integrity Frequently Asked Questions

o  Validation Master Plan

o  Risk Based Assessment

o  Complete Validation for a System (software development lifecycle)

o  Automated Test Tools

o  Infrastructure Requirements

o  Change Control

o  SOPs.

https://www.fda.gov/downloads/drugs/guidances/ucm495891.pdf

Article on “A Tour of the FDA”

A tour of the FDA is something like a snapshot of what the FDA does. The importance of the FDA can never be understated: It regulates products from the proverbial pin to airplane in the food, medical devices, pharma and healthcare industries, which touch almost every aspect of American lives. The products that the FDA regulates account for about a trillion dollars, which make up about a quarter of all goods traded in the US.

So, what is a tour of the FDA like?

A tour of the FDA helps to get a broad understanding of the this regulatory body and get some idea of the various departments it has, as well as the functions of these departments. To get an understanding of what the FDA does, a reference to its mission statement could give some direction:

“(The) FDA is responsible for protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.” This is just the opening line of the FDA’s mission statement. Reference to its other statements, which have now included a reference to containing terrorism, will serve as a good guide to a tour of the FDA. In short, the FDA regulates nearly every item used and consumed by the American public.

The history of the FDA

The legal sanction for carrying out its mission is mandated by the Federal Food, Drug and Cosmetic Act (FD&C Act). An amazing fact that a tour of the FDA reveals is that it is one of the oldest regulatory bodies in the world, with its earliest jurisdiction having covered regulation of drugs in the year 1848. The Department of Agriculture, to which President James Polk appointed noted chemist Charles Wetherill, can be considered the earliest endeavor to regulate medical products of daily use in the US.

How is the FDA organized?

A tour of the FDA is incomplete without a reference to the way it is organized. Its structure consists of this hierarchy:

  • Office of the Commissioner
  • Office of Foods and Veterinary Medicine
  • Office of Global Regulatory Operations and Policy
  • Office of Medical Products and Tobacco
  • Office of Operations

Under these broad heads, a tour of the FDA shows the way into which it is divided into several offices and organizations. Important among these include:

  • Office of Regulatory Affairs (ORA)
  • Center for Food Safety and Applied Nutrition (CFSAN)
  • Center for Drug Evaluation and Research (CDER)
  • Center for Biologics Evaluation and Research (CBER)
  • Center for Devices and Radiological Health (CDRH)
  • Center for Devices and Radiological Health (CDRH)
  • National Center for Toxicological Research (NCTR)

Want to know more: Article on “A Tour of the FDA”

Tips and Suggestions on interacting with FDA Officials and Premarket Approval (PMA)

Preparing premarket submissions that win regulatory approval is a complex task, even for the most seasoned professional in the medical devices industry. This is because of the highly stringent nature of the regulatory approval pathways, namely the Premarket Approval (PMA) process and FDA regulatory 510(k) clearance.

What makes preparing premarket submissions that win regulatory approval challenging? It is the fact, acknowledged by the FDA itself, that the PMA is the most stringent type of device marketing application required by the FDA. The PMA should be secured from the FDA before the company markets the medical device. The FDA gives its approval of the PMA for a Class II medical device only after it determines that all the elements necessary for assuring that the application has enough scientific confirmation that it is safe and effective for the intended uses it is going to be put to. Preparing premarket submissions thus is an onerous task by any stretch of imagination.

Another element of preparing premarket submissions that win regulatory approval

Another aspect of preparing premarket submissions is the 510 (k). The 510 (k) is essentially a kind of premarket submission that is made to the FDA to show that the device that a manufacturer intends to market is at least as effective and safe as a legally marketed device of its equivalence, already in the market, that is not subject to PMA. The FDA calls this principle the substantial equivalency (SE) and the device that is used as the reference for equivalence, the predicate device. The requirements governing SE are contained in 21 CFR 807.92(a) (3).

On top of all these, regulatory professionals have the responsibility of creating preparing premarket submissions that should not only convincingly demonstrate the ways of stating and explaining regulatory arguments for their device to the U.S. FDA reviewer for getting the approval; they should also be presentable and well-organized, without being cluttered or confusing.

Professional trainings for preparing premarket submissions that win regulatory approval

Given all these, it goes without saying that a completely thorough understanding and knowledge of the relevant U.S. FDA laws, regulations and requirements is absolutely necessary for regulatory professionals. This in-depth understanding can be had only from thorough training, which is indispensable if the medical device company is to win a clearance or approval.

The ways by which to do this is the core learning a two-day seminar from GlobalCompliancePanel, a leading provider of professional trainings for the regulatory compliance areas, will impart. The Director of this seminar is Subhash Patel, a very senior regulatory professional and founder of New Jersey-based MD Reg Consulting LLC, which serves medical device industry clients in all aspects of global regulatory affairs specific to their needs.

To enroll for this highly valuable training session on how to successfully prepare 510(k)/Pre-IDE/IDE and PMA premarket submissions that secure clearances and approvals from the FDA, please register for this seminar by visiting Tips and Suggestions on interacting with FDA Officials and Premarket Approval (PMA) . This seminar has been pre-approved by RAPS as eligible for up to 12 credits towards a participant’s RAC recertification upon full completion.

The grasp needed for preparing premarket submission that win regulatory approval

At this seminar, Patel will demonstrate the grasp that regulatory professionals in the medical devices industry need for working with the FDA officials during the review and approval process of their submission. He will offer a complete understanding of the major aspects of FDA premarket submissions.

While knowledge of the regulatory process is one thing; medical device companies also need to know how to set and state regulatory arguments for their device in a most convincing manner to the FDA reviewer. This knowledge will be part of this course. In the process of explaining how to prepare premarket submissions that win regulatory approval; Patel will also offer tips and suggestions to participants on how to work effectively with the U.S. FDA officials during review and approval process of their submission.

During the course of these two days, Patel will cover the following core elements of how to prepare premarket submissions. He will explain the following:

o  History and background of U.S FDA Laws and Regulations

o  Classify Your Device

o  Choose the Correct Premarket Submission for your device

o  Compile the Appropriate Information for your Premarket Submission

o  Author and Prepare your Premarket Submission

o  Submit your Premarket Submission to the FDA

o  Interact with FDA Staff during Review and Approval

o  Complete the Establishment Registration and Device Listing