What is risk-based monitoring?

Sponsors of clinical studies adapt many methods that are aimed at reducing the complexity of clinical trials. They also look for methods by which they can increase the efficacy of the results, while keeping the costs low. Risk-based monitoring is one of these methods.

How is risk-based monitoring understood?One can understand risk-based monitoring in several ways. This varied understanding is because there is no one definition or application of this concept. Risk-based monitoring is a method of evaluating and preventing risk in a clinical trial. This broad definition of course, conceals more than it reveals, since risk-based monitoring can happen in a number of ways and can be applied in a number of areas concerning the clinical research.

FDA and EMA guidelines on risk-based monitoringIn 2011, the FDA, as well as the European Medicines Agency (EMA) their respective sets of draft guidance aimed at helping sponsors of clinical research get a better understanding of the regulatory requirements and obligations for the conduct clinical trials using risk-based monitoring. However, these guidelines were not specific. Moreover, they did not make any procedure or methodology or rule relating to risk-based monitoring mandatory. Since these guidelines on were more or less prescriptive and suggestive by nature; they did not address the core issue relating to risk-based monitoring, leaving the topic rather hazy.

Since this is the current state of risk-based monitoring regulations, most clinical trials sponsors have stuck to the traditional mode of risk-based monitoring. These generally include:

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The importance of cloud technology to risk-based monitoringSince all these are generally disparate from each other; risk-based monitoring has now required more and more extensive use of technology that will enable his. Risk-based monitoring has now increasingly become technology-driven and technology reliant. As new technologies such as the cloud gain more acceptance; risk-based monitoring has grown with it, since it will help keep track of the various activities at various levels and helps integrate these in real time.

 

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FDA Warning Letters – an understanding

As the primary regulator of the biological, healthcare, life sciences and other related industries; the FDA has power and authority over how its work is carried out. FDA Warning Letters are among the primary mediums through which it enforces its authority.

The FDA issues a Warning Letter to a company when it determines, following its inspection of a facility from an industry that it regulates, that the facility is violating some or other terms of the provisions of the FDA Act. The FDA Act is a legislation that gives the FDA the authority to carry out its inspections.

fdaWarningLettersThe issuance of an FDA Warning Letter is an indication that the facility is practicing some degree of nonconformity. A Warning Letter is among the FDA’s strongest tools of ensuring voluntary compliance from organizations with the provisions of the FDA Act.

The FDA publishes on its website any deviances of regulatory significance that it discovers from a facility during its investigations. In its viewpoint, a deviation of regulatory significance is one that leads to enforcement actions if the facility fails to carry out corrective action of whatever violations the FDA has documented.

Types of Warning Letters from the FDATo enable the public and concerned parties to view the Warning Letters it issues from time to time; the FDA has classified these on its website in the following manner:

fdaWarningLettersA General Warning Letter is one that is issued to a company in whose activities the FDA notes significant variations from the principles laid out in the FDA Act. The Warning Letter carries a description of the variation or violation that the manufacturer has been practicing, along with a description of what actions needs to be taken to correct it.

Tobacco Retailer Warning Letters are those that are issued to manufacturers of products made out tobacco, such as cigarettes, smokeless cigarettes and related ones, who are found to be violating the provisions of the FDA’s Tobacco Control Act and with provisions of Title 21 of the Code of Federal Regulations, Part 1140 (21 C.F.R. Part 1140).

Drug Marketing and Advertising Warning Letters (and Untitled Letters to Pharmaceutical Companies) are those Warning Letters that the FDA website sorts out by month and consist only of Division of Drug Marketing and Communications and Drug Warning Letters. This kind of Warning Letter is issued to sellers of prescription drugs online when they are found to violate terms set out by the FDA.

Warning Letter closeout program
fdaWarningLettersWhen the FDA issues a Warning Letter to a facility that comes under the various classifications; it follows up with it from time to time to ensure that the suggestions it advises are carried out. When the facility has carried out the necessary corrective actions; the FDA issues the Warning Letter Closeout, which closes the matter associated with the Warning Letter until the next FDA inspection.

Methods of issuing Warning LettersIt is only when it discovers violations that the FDA issues Warning Letters. It is through inspections that it discovers violations, from which Warning Letters follow. However, the FDA can also issue Warning Letters to facilities about which its receives complaints of wrongdoing from state personnel.

An FDA Warning Letter is not an enforcement action
fdaWarningLettersIn the perspective of the FDA; a Warning Letter is of an informal and advisory nature. An FDA Warning Letter is a description of the violation observed at a facility; but this in itself does not make the FDA take enforcement action. Rather, through a Warning Letter, the FDA advices the organization on what steps it has to take in order to rectify and correct the reasons for which the Warning Letter was issued. An FDA Warning Letter offers the organization enough opportunity to take corrective action that is of a voluntary and appropriate.

 

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Tougher FDA import rules are aimed at putting strict controls on imports

Tougher FDA import rules are aimed at putting strict controls on imports 3

Import rules are very rigid and strict in the US, because products of any type and variety can enter the US. The US being the world’s largest consumer economy; manufacturers and marketers from around the world vie for a chunk of this market. The FDA, being the agency that regulates a myriad of products, has rules for imports to the US, which have been toughened of late.

The total number of lines imported to the US more than doubled from 2006, when it was at 15 million lines, to over 35 million in 2016 (The FDA considers a distinct product within a shipment as a line). The FDA’s vigil on products that enter the US and by consumed by Americans is quite understandable: in the fiscal year 2016; among all the imported lines that entered the US; about half consisted of medical devices, and about a third, of foods, both of which are very crucial to human health.

Rules relating to import of drugs
tougherImportRulesForFdaAnother core component of US imports is drugs, which is also extremely crucial to humans. The FDA has very stringent rules for the import of drugs. it does not consider the regulatory approval of any other regulatory agency as acceptable in the US. It considers only regulation of drugs by it as the criterion for accepting imports of drug products. In some cases, however, it relaxes these rules, subject to the condition that the stock of the drug may only be shipped for three months of treatment at a time:

tougherImportRulesForFdaThe FDA has now collaborated with the Customs and Border Patrol Service (CBP), putting even tougher import rules in place. The FDA has not only got tougher in its import rules; it has become even more sophisticated in tracking and detecting importers who violate its rules. New rules require importers to submit many kinds of information and to adhere to set procedures laid out by the government in this regard.

Strict when it comes to penal actions, tooWith the FDA tightening its grip on imports; a foreign manufacturer whose products come under an FDA Import Alert is up against a hill when it comes to importing its products into the U.S. The FDA and the CBP can delay, detain or refuse its shipment or detain a shipment of a company that violates these rules.

The consequences of having a shipment detained 
tougherImportRulesForFdaThe consequences of having a shipment detained by the FDA can bring its adverse consequences:

  • Tougher FDA import rules arm the FDA with the power to begin a potentially long drawn out and expensive legal process
  • It will have very little time to respond to queries from the FDA or the CBP. Not responding in time invites further penalties
  • A fine that is three times the value of the goods contained in the shipment may be imposed
  • At times, their product can be seized ty the government and destroyed
  • If a violating importer receives a release but cannot locate the product that has been sold, it should bring the products back to the port of entry and face adverse legal steps

A few remedial measures 
tougherImportRulesForFdaThe only real antidote to avert profound consequences of the FDA’s tougher import rules is to be aware of the rules in their entirety. A company that has a sound understanding of the legal and prior notice information requirements has a safe passage compared to a company that doesn’t.

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Best Practices in Vendor Risk and Compliance Management

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Best practices in vendor risk and compliance management need to be inculcated by vendors who deal with them because of the enormous risk their activities carry. Implementation of best practices in vendor risk and compliance management goes a long way in checking risks and with it, the adverse fallouts of a vendor management program.

First of all, why do organizations have a vendor partnership? It is because this kind of arrangement helps them to take care of their logistics and other aspects of their business in a much more streamlined and economical fashion, and this in turn helps them to concentrate and focus on their core business better. A strategic vendor partnership helps organizations manage their products and services better, and more economically. The root to this is inculcation of best practices in vendor risk and compliance management.

vendor-risk-and-compliance-managementThe importance of best practices in vendor risk and compliance management can be understood from the fact that when companies outsource their operations, or particular parts of them, or some of their activities, this does not include organizational responsibility. So, the onus of ensuring compliance with regulatory guidelines and making sure that the vendor has implemented best practices in vendor risk and compliance management lies squarely with the organization that outsources.

Burden is on the organization that hires vendorsThis places a heavy responsibility on them, since of late regulatory guidelines for best practices in vendor risk and compliance management have become all the more stringent. While outsourcing part of their activity or operations or logistics or even parts of product development to vendors; companies have to be very sure that they are in tune with best practices in vendor risk and compliance management.

vendor-risk-and-compliance-managementThe basis to implementing best practices in vendor risk and compliance management is to get a clear comprehension of vendor responsibilities. Many organizations make the mistake of assuming that best practices in vendor risk and compliance management need to be implemented only at the stage of selecting the vendor. This is disastrous thinking, because selection of the vendor is just the beginning of the outsourcing program. These organizations have to make sure that best practices in vendor risk and compliance management is a continuous program and activity, and hence utmost care has to go into managing them at all times.

Reasons for increased need for implementation of best practices in vendor risk and compliance managementThe need for adaption and implementation of best practices in vendor risk and compliance management has become all the more acute and necessary in view of the following factors:

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FDA Requirements for ensuring Premarketing Clinical Trial Safety

FDA Requirements for ensuring Premarketing Clinical Trial Safety 2

The FDA has set out requirements for sponsors and organizations that carry out clinical trial to ensure premarketing clinical trial safety. This is a very vital requirement because this is the stage at which the database that goes into clinical trials is formed. Its integrity and safety is an important ingredient for assessing the risks and benefits that go into the clinical trial, and errors need to be identified and corrected at this stage. Wrong data could lead to disastrous consequences for the study, the subjects that are part of it, the organization and eventually, patients.

Basic nature of FDA requirements for premarketing clinical trial safety

FDA Requirements for ensuring Premarketing Clinical Trial Safety 1

The FDA has a set of requirements for premarketing clinical trial safety, but these are mostly informal and loose. They are more of an advisory nature than being stringent regulatory requirements that are legally enforceable. Most FDA guidance is on a case-by-case nature.

FDA Requirements for ensuring Premarketing Clinical Trial Safety 4

Basically, the FDA’s guidance is based on its working with large to very large clinical trials. It has thus far not seriously considered working with small groups for assessing premarketing clinical trial safety. At its barest, the FDA seeks to:

  • Advise sponsors or organizations undertaking the clinical trial about ways by which their data collection can be simplified so as to ensure that it is neither too huge nor too small, and should lead to giving insights about the drug’s safety. Essentially, the FDA guideline on premarketing clinical trial safety seeks to prevent sponsors from collecting data that is not relevant.
  • Get sponsors to consult the FDA’s review division for its premarketing clinical trial safety.
The FDA has different requirements for different kinds of studies that relate to clinical trials. For example:

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The FDA’s requirements for non-IND Foreign Clinical Studies

The FDA grants marketing approval for certain types of medical products whose application is the result of foreign clinical studies, provided the products and the clinical studies meet certain conditions. The types of medical products

The FDA's requirements for non-IND Foreign Clinical Studies 2

that are permitted under this system of foreign clinical studies include:

  • A human drug
  • A biological drug
  • A medical device

The guidelines for foreign clinical studies requirements

The guidelines under which the FDA accepts medical products for approval when they are the result of foreign clinical studies are spelt out in various sections of 21 CFR.

Any foreign clinical study has to be meet requirements of 21 CFR Part 312or 21 CFR Part 812, which relate to studies conducted under an Investigational New Drug Application (NDA) or Investigational Device Exemption (IDE) respectively, just the same way in which American companies too have to

In case a foreign clinical study is not conducted under an IND; the FDA will still accept it, so long as it fulfills the ethical principles set out in the Declaration of Helsinki, or is in accordance with the laws of the respective country from which the study originates, based on whichever of these two offers stronger protection of the subjects of the study.

Highlights of the Helsinki Declaration

The FDA's requirements for non-IND Foreign Clinical Studies 1

The World Medical Association adapted the Helsinki Declaration from the time it was passed in 1964. In 1975, given the popularity of the Declaration in guaranteeing humane protection of human subjects in a clinical study; the FDA adapted the principles of the Helsinki Declaration as the basis for accepting non-IND compliant drugs. This Declaration has been revised a few times, although the FDA is yet to include the latest of these, that of October 2000, into its regulations.

Points of significance

The Investigational New Drug Applications mechanism in the USA

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The IND is a process which gives the sponsor the opportunity to start marketing across the States of the US without having to complete the formal process. it also gives the patient the assurance that the drug that is being administered may not have gone through the full regulatory process as yet, but is as effective as one that is already in the market. The FDA has three mechanisms in place for submission of an IND.

Present Federal law requires a manufacturer who wants to market a drug in the US to subject the drug to an approved marketing application before it gets transported and/or distributed for interstate commerce, i.e., within the different States in the US.

Since it is very likely that the sponsor of a clinical trial may want to ship the investigational drug to clinical investigators across several states, it is but natural that the sponsor would look for exemption from this legal requirement. The Investigational New Drug (IND) Applications in the USA is the mechanism through which this exemption issues from the FDA to the sponsor.

investigationalNewDrugApplicationsInTheUsaWe can understand the Investigational New Drug Application this way: it is a request made by the sponsor of a clinical study with the FDA asking for its authorization to administer a biological product or an investigational drug to humans before the product goes through interstate shipment. The IND application should also be made before administering a drug that is not the same as an approved New Drug Application or Biologics/Product License Application.

The rationale behind filing Investigational New Drug Application

 

Ensuring a drug’s safety for use in humans is the basis for the entire idea of filing an Investigational New Drug Application. This is the prelude to the steps for its commercialization. By paving the way for further actions such as data collection; the Investigational New Drug Application is often the predecessor step for reinforcing the drug’s safety. An Investigational New Drug Application can be understood or taken as some kind of assurance or guarantee that when the drug that is at this stage of studies is administered on humans; it is not harmful and does not carry risks.

Ensuring a drug’s safety for use in humans is the basis for the entire idea of filing an Investigational New Drug Application. This is the prelude to the steps for its commercialization. By paving the way for further actions such as data collection; the Investigational New Drug Application is often the predecessor step for reinforcing the drug’s safety. An Investigational New Drug Application can be understood or taken as some kind of assurance or guarantee that when the drug that is at this stage of studies is administered on humans; it is not harmful and does not carry risks.

The FDA’s roleinvestigationalNewDrugApplicationsInTheUsaThe FDA’s comes into the picture when the sponsor who files an Investigational New Drug Application wants to test the effect on humans of molecules that it has screened and identified. At this stage, the status of the molecule changes into a new drug that is subject to the requirements set out by the regulatory system.

Kinds of INDsThere are three types of Investigational New Drug Applications:

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Elements of an Investigational New Drug Application
investigationalNewDrugApplicationsInTheUsaThe FDA requires an Investigational New Drug Application to contain the following:

  • Studies carried out for testing animal pharmacology and toxicology
  • Information about the manufacturing aspects of the drug
  • Information about the clinical protocols and investigator of the Investigational New Drug Application

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