TARGET AUDIENCE

• The sponsor of the clinical trial: the sponsor is usually a pharmaceutical company who develops prescription drugs, including biological drug products.
• The clinical investigator: the clinical investigator is generally a physician contracted by the sponsor to recruit trial subjects and conduct procedures outlined in a clinical protocol.
  

FDA LAWS AND REGULATIONS REFERENCED

• Title 21 of the Code of Federal Regulations, part 16 (Regulatory Hearing Before the Food and Drug Administration); referred to as 21 CFR Part 16; http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr&sid=e52a07612e9568a459c0124abc9b4bbb&rgn=div5&view=text&node=21:1.0.1.1.12&idno=21#21:1.0.1.1.12.1.31.1
  
• Title 21 of the Code of Federal Regulations, part 50 (Protection of Human Subjects); referred to as 21 CFR Part 50; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=50
  
• Title 21 of the Code of Federal Regulations, part 56 (Institutional Review Boards); referred to as 21 CFR Part 56; http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=312&showFR=1&subpartNode=21:5.0.1.1.3.4
  
• Title 21 of the Code of Federal Regulations, part 312 (Investigational New Drug Application); referred to as 21 CFR Part 312;http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=312

OTHER GUIDANCES REFERENCED

• Guidance for Industry: Formal Meetings with Sponsors and Applicants,http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm153222.pdf

RATIONALE

When the Food and Drug Administration (FDA) becomes aware of investigator misconduct during a clinical trial they will notify the investigator by issuing a Form FDA 483 (Inspectional Observation) or a warning letter. If the investigator does not quickly correct the violation(s) cited or continues the behavior or practice, the FDA will take the investigator to federal court and/or move to disqualify the investigator. However these proceedings often take months or years. Therefore, in order protect trial participants it may be necessary for the FDA to stop the clinical trial immediately. They do this by issuing a clinical hold.

Guidance for Industry and Clinical Investigators: The Use of Clinical Holds Following Clinical Investigator Misconduct contains a high level description of the clinical investigators’ responsibilities regarding the conduct of a trial and actions the FDA can take to protect trial participants in the event of investigator misconduct. The guidance also provides examples of the types of misconduct that will lead to a clinical hold.

In general, this guidance does not provide specific recommendations to the investigator or sponsor; instead it provides insight into what a clinical hold is, when it will be applied, and when it will be removed.

THE CLINICAL HOLD

• Before initiating clinical hold the FDA will evaluate: (1) the impact the violation will have on the participants safety, rights and welfare and (2) if they are comfortable that the evidence of misconduct is valid.
  
• The FDA notifies and works with the sponsor prior to imposing a clinical hold in an attempt to resolve the issue(s).
  
• A clinical hold may be partial or complete. A clinical hold is considered complete when all protocols included under an IND are stopped. A partial clinical hold is when only 1 protocol under an IND is or delayed, or the misconduct does not affect all sites participating in a multi-center trial.
  
• Depending on the severity or scope of the misconduct, a clinical hold may apply to only one protocol being conducted by the investigator or all clinical trials being conducted by the site.
  
• Examples of misconduct that may lead to a clinical hold include (1) not reporting serious adverse events and (2) enrolling inappropriate participants (ie, those who have pre-existing conditions that would make it harmful to receive the investigational product being studied).
  
• When a clinical hold is in place the investigator cannot recruit new trial participants. Participants already enrolled in the trial must stop the investigational product unless the FDA deems stopping would be harmful to the participant.
  
• If misconduct is identified that does not affect participant safety a clinical hold may not be imposed.
  
• The clinical hold will be removed when the issues regarding investigator misconduct have been resolved.

IMPACT

This guidance is beneficial to investigators and sponsors in that it outlines the actions that the FDA may take when they become aware of investigator misconduct. What this guidance does not address is the sponsors’ responsibility for monitoring a clinical trial. Monitoring of a trial by the sponsor begins before the trial starts and continues through the end of the trial. The sponsors’ responsibilities include (1) ensure the investigators and their staff are qualified to conduct a trial, (2) collect pre-trial documentation, (3) conduct protocol specific training, (4) ensure informed consent is being collected from all participants and all data is being accurately collected and reported, and (5) Institutional Review Board (IRB) approvals have been granted. So in essence, the sponsor is more likely to identify investigator misconduct than the FDA.

Per ICH E6 - 5.20.2 (http://www.cc.nih.gov/ccc/clinicalresearch/guidance.pdf), if a sponsor identifies a situation similar to that which warrants a clinical hold as described in Guidance for Industry and Clinical Investigators: The Use of Clinical Holds Following Clinical Investigator Misconduct, they should terminate the investigators’participation in the trial and notify the FDA. Personally I think this guidance should include that recommendation.

-- Tracey Fletcher 

This draft guidance was released in August 2000 and is available a thttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122858.pdf.

This guidance applies to applicants or sponsors who must file new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements to these applications, as well as those who file drug substance and drug product Type II drug master files (DMFs).

Laws and regulations referenced. Because this guidance relates to the broad areas of analytical procedures and methods validation to document the chemistry, manufacturing, and controls (CMC) section of applications, several laws and regulations are involved:

• 21 CFR 211.165(e)
• 21 CFR 211.194(a)(2) and (10)
• 21 CFR 312.23(a)(7)
• 21 CFR 314.50(d)(1) and (e)
• 21 CFR 314.94(a)(9)(i)
• 21 CFR 601.2 (a) and (c)(1)(iv)
• 21 CFR 610.20.

Broadly, this guidance refers to compliance with

• current Good Manufacturing Practices (cGMPs) (21 CFR part 211)
• Good Laboratory Procedures (GLPs) (21 CFR part 58)
• compendial procedures under section 501(g) of the Food, Drug, and Cosmetic Act.

The guidance also references other FDA guidances (among others listed in the References lines 1159 ff):

• Content and Format of Investigational New Drug Applications for Phase I Studies
• INDs for Phase 2 and 3 Studies of Drugs
• Validation of Chromatographic Methods.

The guidance references the International Conference on Harmonization (ICH) guidances (among other listed in the References lines 1190 ff):

• Q2 Text on Validation of Analytical Procedures
• Q2B Validation of Analytical Procedures: Methodology
• Q3Q Impurities in New Drug Substances.

Finally, by reference, the guidance cites the current version of the US Pharmacopeia–National Formulary(USP–NF).

Summary. Applicants, as defined above, must provide FDA with accurate and reliable documentation about analytical procedures and methods validation, along with samples, if appropriate, to ensure the identity, quality, purity, and potency of drug substances and drug products. Although this may at first seem straightforward, an applicant’s challenge is to show that, eg, clinical study batches of a drug substance and drug product used in 1-kg (or smaller) batches manufactured in, eg, New Jersey are equivalent to metric tons of hypothetically equivalent product manufactured years later in places as diverse as Puerto Rico, India, or China.

In order to achieve these goals, applicants use analytical procedures that comply with compendial guidelines (eg, chromatography, spectrophotometry, protein analysis, and others). These methods must be validated, which is defined as the “process of demonstrating that analytical procedures are suitable for their intended use.” Analytical procedures can include those specified in General Chapters of the current USP–NF, or they may be the applicant’s properly validated and approved methods. The former require only compliance, but the latter require full validation. That is, methods validation can be satisfied by demonstrating compliance with the current USP–NF methods or submission of a full validation package.

Rationale. In all cases, in the CMC sections of applications the applicant’s objective is to demonstrate that drug substances, drug products, excipients, and manufacturing are equivalent to or better than those identified in the applicant’s approved filing (NDA, ANDA, BLA, and so forth). If the applicant has changed materials, manufacturing site or procedures, or analytical technologies (among other changes), the applicant must demonstrate that drug substances and products retain acceptable identity, quality, purity, and potency.

Variations in a drug’s quality attributes can result from many factors (changes in active ingredient impurities, different excipients, different manufacturing equipment or procedures, and many others). After approval, clinical trials materials manufactured in small batches must be scaled up to production batches, and applicants must ensure that the approved product has at least the quality attributes of the approved product. This guidance helps applicants fulfill these requirements.

Resulting recommendations. Applicants must demonstrate that their analytical procedures and validation are under control and that their currently marketed products are equivalent to those in the approved application. Applicants can do so by showing compliance with regulatory/compendial procedures or validated alternative analytical procedures.

In effect, applicants may receive a bulk shipment of active pharmaceutical ingredient. This material must be tested by an assay to ensure its identity, quality, purity, and potency. The assay used is part of the sponsor’s application (NDA, ANDA, etc) and includes specification, defined as tests, procedures, and acceptance criteria. The tests may include, eg, chromatography carried out according to defined procedures involving type of column, reagents, and operating conditions, and predefined test criteria (eg, amount of active ingredient detected, impurity profile, and other characteristics).

If these tests follow the current USP–NF, the sponsor needs only to ensure that the assay was carried out in compliance with USP–NF. Such quality assurance is satisfied by documentation that analysts followed the compendial procedures. If the sponsor develops a new approach or varies from established compendial procedures, this sponsor must present detailed evidence, as outlined in this guidance, that the new assays or procedures are equivalent to or are better than USP–NF procedures.

An important component of demonstrating compliance with the approved application (NDA, ANDA, BLA, etc) is showing equivalence to a drug substance or drug product standard. The standard is either a sample of the sponsor’s reference material that, according to the guidance, is deposited with FDA and is also retained by the company as a house standard, or the applicant and FDA use a USP reference standard. In either case, the reference standard is a highly purified and qualified sample of the reference substance or product that is defined as the standard that shows drug substance or drug substance identity, quality, purity, and potency.

The guidance describes various quantitative tests for impurities, not all of which apply to a specific product. But the guidance is useful in helping applicants determine which tests they must perform, how often, and with what accuracy. In addition, because consistent quality is the objective, validation is an ongoing process that must be continuously monitored. Applicants must perform trend analysis to ensure that their processes, procedures, and activities are not drifting out of specification.

Impact. This guidance is a key document that shows applicants how they can demonstrate compliance with laws and regulations regarding analytical procedures and validated methods. Because each drug substance and drug product is unique, one can expect variation in types of analytical procedures, acceptance criteria, and validation from drug to drug (eg, innovator product vs generic drug or small molecules vs biotech products). As noted, the CMC section of applications helps ensure that regulators, manufacturers, and others can test drug substances and drug products meet standards of identity, quality, purity, and potency. This guidance does not speak to drug efficacy or mechanisms of action, but it does ensure that drug manufacturing is of consistent, well-defined quality.

[NOTE: This blog uses the terms test, procedure, and method loosely and often synonymously. In metrology they are distinct, as are accuracy, repeatability, intermediate precision, and robustness, which all are carefully defined components of measurement science. Those who are responsible for compliance with this guidance must be well versed in metrology.]

-- Stefan Schuber

• required (i.e., a postmarketing requirement) under the new law


• agreed-upon as a commitment (i.e., a postmarketing commitment)
  

Resulting Recommendations:

The FDA requires a postmarketing study or clinical trial as a postmarketing requirement if the following conditions are met:

1. the FDA has appropriate scientific data (including data on chemically- or pharmacologically-related drugs) as evidence
2. before requiring a postmarketing study, the FDA has found (a) adverse event reporting undersection 505(k)(1) and the new pharmacovigilance system to be established under section505(k)(3) of 21 U.S.C. 355(0) or (b) a postmarketing study will be insufficient to meet condition 3 below
3. when a study or clinical proposes to (a) access a known serious risk related to the drug, (b) access signals of (a), and/or (c) identify unexpected serious risk when available data suggests a potential serious risk

Postmarketing requirements may include but are not limited to:

• observational pharmacoepidemiology studies evaluating a serious risk related to drug exposure or to access/quantify factors (e.g., drug dose, time of exposure, or patient characteristics) that may influence the risk of serious toxicity)
• clinical trials with a safety primary endpoint with prespecified assessments
• animal safety studies acessing specific end-organ toxicities (e.g., carcinogenicity, reproductive toxicity)
• in vitro laboratory safety studies
• pharmacokinetic studies or clinical trials in the patient population specified in the drug label or in a subpopulation potentially at risk for toxicity from high drug exposure
• drug interaction or bioavailability studies or clinical trials when scientific data indicate a potential sereious safety risk

A postmarketing study or clinical trial that an applicant of a prescription drug or biological product agrees to undertake without a postmarketing requirement from the FDA is a postmarketing commitment.

Postmarketing commitments may include:

• drug and biologic quality studies (e.g., manufacturing, stability, immunogenecity) without a safety endpoint
• pharmacoepidemiology studies accessing the natural disease history or background adverse event rates
• clinical trials with a primary efficacy endpoint
  

Impact: Whenever a marketing application for a new prescription drug (including biological products) is filed to the FDA, the FDA will send to the applicant a list of possible postmarketing requirements and postmarketing commitments to be discussed and finalized with the FDA review team. Once the applicant agrees to conduct the agreed upon postmarketing requirements and/or commitments under an agreed upon timetable, the applicant must periodically report on the status of these studies or clinical trials. If an applicant does not comply with the timetable, periodic reporting, or other requirements in section 505(o)(3)(E)(ii), the FDA will be able to enforce these requirements by issuing an unapproved drug charge, a misbranding charge (21 U.S.C. 332(z)), or civil monetary penalties (21 U.S.C. 333(f)(4)(A)).

With applicants of new prescription drugs being required to conduct postmarketing safety studies and clinical trials, the FDA will have more data to identify and access potential safety risks and consequently the patient population taking these new prescription drugs will be better protected from these potential safety risks.

-- Jennifer Han

• Title 45 of the Code of Federal Regulations, part 46 (Protection of Human Subjects); referred to as 45 CFR Part 46
• Title 45 of the Code of Federal Regulations, part 160 (General Administrative Requirement); referred to as 45 CFR Part 160
• Title 45 of the Code of Federal Regulations, part 164 (Electronic Code of Federal Regulations; General Provisions), subparts A and E; referred to as 45 CFR Part 160
• Title 21 of the Code of Federal Regulations, part 50 (protection of Human Subjects); referred to as 21 CFR Part 50
• Title 21 of the Code of Federal Regulations, part 56 (Institutional Review Boards); referred to as 21 CFR Part 56

OTHER LAWS AND RULES REFERENCED

• Health Insurance Portability and Accountability Act of 1996 (HIPAA) (Public Law 104-191)
• The Standards for Privacy of Individually Identifiable Health Information (the Privacy Rule)

OTHER GUIDANCES REFERENCED

• 65 Federal Register 81081 (Guidance for Industry: Recognition and Use of a Standard for theUniform Labeling of Blood and Blood Components); referred to as 65 FR 81081
• Guidance for Industry: E6 Good Clinical practice: Consolidation Guidance (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf)
• Premarketing Risk Assessment (Premarketing Guidance) (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm126958.pdf)
• Good Pharmacovigilance practices and Pharmacoepidemiologic Assessment (Pharmacovigilance Guidance) (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126834.pdf)
• International Conference of Harmonization (ICH) guidance E2E: Pharmacovigilance Planning (E2E guidance) (http://www.fda.gov/RegulatoryInformation/Guidances/ucm129411.htm)

RATIONALE

The process of managing the benefit-risk balance takes place throughout the lifecycle of a drug. The evaluation of risk, and benefit-risk balance, starts during the early development of a drug and continues long after the drug is marketed. There are 4 steps to managing the risk: assessing the benefit-risk, developing a plan to minimize the risk, evaluating whether the plan is working, and making adjustments in the plan to ensure the drugs maximum benefit is achieved with the lowest amount of risk to the patient.

Guidance for Industry: Development and use of Risk Minimization Action Plans contains the FDAs recommendations for developing a strategic safety program or RiskMAP. Not all drugs need a RiskMAP since routine monitoring is sufficient for most. The guidance provides the FDA’s suggestions for how to determine if a RiskMAP is appropriate, and how to design and evaluate a RiskMAP. In addition there are recommendations for how to communicate with the FDA during the development of the RiskMAP, along with when and how to report the results.

RECOMMENTATIONS

Determine when a RiskMAP is appropriate

The decision that a RiskMAP is appropriate can be made at any time (during early development, clinical trials, and postmarketing). The sponsor should use evidence-based data when determining if a RiskMAP is needed. The evaluation of need should be ongoing as more data becomes available. The FDA also has the right to recommend a RiskMAP if they assess a need based on their review of available data.

How to Create RiskMAP

Establish goals and objectives: A goal is the outcome the RiskMAP is trying to achieve. The objective is how the goal will be obtained. For example, the goal is that patients must not become pregnant while using the drug. The objective is to communicate to the patient that they should not become pregnant while taking the drug.

Decide which tools to use for achieving goals and objectives: A tool is the mechanism that will be used to obtain the goal and objective. The FDA recommends 3 categories of tools: targeted education and outreach (ie, patient medication guides, prominent professional or public notifications), reminder systems (ie, consent forms, limitations on refills of a product), and performance-linked access systems (ie, requiring specific lab tests periodically be performed to establish safe use).

Assess the effectiveness of tools and the RiskMAP: To assure effectiveness, the FDA recommends that the sponsor periodically assess the overall RiskMAP and the tools used. The RiskMAP and tools can be changed at any time if it is felt the goals and objectives of the plan are not being met.

Communication with the FDA

The FDA is always available for consultation regarding the design and appropriateness of a RiskMAP. Within the guidance are specific recommendations for who the sponsor should contact within the FDA. Also provided within the guidance are the FDA’s suggestions regarding the content of a RiskMAP being submitted to them for review.

IMPACT

In most cases, product labeling, and adverse event reporting and monitoring are sufficient for the assessment of risk. However, there are instances when more aggressive measures must be taken to establish a benefit-risk balance. Although this guidance is the FDA’s current thinking regarding the development and use of a RiskMAP and following their suggestions is not mandatory, in my experience sponsor’s take a regulatory body’s “thoughts” seriously. This guidance is important in that it gives the sponsor the ability to provide a plan that will meet the FDA’s expectation. The guidance is also important in that it lets the sponsor know that the FDA will request a RiskMAP if they feels it is warranted based on their review of the safety data. Thus the sponsor is reminded that they are being watched!

--Tracey Fletcher