Guidance for Industry and Clinical Investigators: The Use of Clinical Holds Following Clinical Investigator Misconduct

This guidance was released as a final guidance in September 2004. It can be found online at
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126997.pdf

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.

Blog 2

Name of Guidance
· ICH Guidance E2C Clinical Safety Data Management Periodic Safety Update Report for Marketed Drugs

Status of Guidance: Draft/Final Guidance
· This guidance the final addendum to E2C Clinical Safety Data Management Periodic Safety Update Report for Marketed Drugs

When was the Guidance released?
· This E2C ICH guidance was released in February 2004. Endorsed by the ICH, November 1996, published by the FDA 1997. It is implemented in some but not all ICH countries

Link to the Guidance
· http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129455.pdf

Target audience
· Pharmaceutical Industry, Regulatory Authorities in the European Union, Japan and US, Marketing Authorization Holders, Medical Writers, Ethics Committee

Laws and Regulations Referenced (and what each law states in relevant part}
· U.S. Department of Health and Human Services
· Food and Drug Administration (FDA)
· Division of Drug Information, HFD-240
· Center for Drug Evaluation and Research (CDER)
· Center for Biologics Evaluation and Research (CBER)

Summary
· The periodic safety update report (PSUR) is a practical tool for summarizing interval safety data particularly covering short periods i.e., six months to one year, for conducting an overall safety evaluation.

Rationale
· The ICH E2C guidance was developed to harmonize PSURs submitted to regulatory authorities in terms of content and format as well as to introduce the concept of international birth date (IBD).

Resulting Recommendations
· Information on all indications, dosage forms, and regimens for the active substance should be included in a single PSUR, with a single data lock point common for all aspects of product use.
· Consistent, examination of the safety information for the active substance(s) in a single document. Relevant data relating to a particular indication, dosage form, or dosing regimen, and safety issues should be presented in a separate section within the body of the PSUR.
· Regulatory authorities should be notified and their agreement at time of authorization, for instances where a separate PSURs may be considered appropriate. For example:
Fixed combinations: Options include either a separate PSUR for the combination with cross-reference to the single agent(s) PSUR(s) or inclusion of the fixed combination data within one of the single agent PSURs.

When an active substance is used in two or more different formulations (e.g., systemic preparations versus topical administration), two or more PSURs, with the same or different IBDs, can be useful.

Impact
· The PSUR is a tool for marketing authorization holders (MAH) to conduct systematic analyses of safety data on a regular basis.
· The PSUR covers ongoing safety issues, and should include updates on emerging and/or urgent safety issues, and major safety signal detection and evaluations addressed in other documents.
· PSURs are of value and importance to all parties in protecting the public health.

Eileen's Blog Post #2

The FDA guidance entitled, Certifications to Accompany Drugs, Biological Product, and Device Applications/Submissions: Compliance with Section 402(j) of The Public Health Service Act, Added By Title VIII of The Food and Drug Administration Amendments Act of 2007 was released in its draft form in 2007 and modified and released on March 5, 2009 (http://www.fda.gov/RegulatoryInformation/Guidances/ucm125335.htm).

Target Audience: Sponsors, Industry, Researchers, Investigators, Food and Drug Administration (FDA) personnel

Laws Referenced: Section 402(j)(5)(B) of the Public Health Service Act (PHS Act), 42 USC §282(j)(5)(B) Title VIII of Food and Drug Administration Amendments Act (FDAAA). The law expands the types of clinical trials and related information that must be submitted to the clinical trial data bank (www.clinicaltrials.gov) managed by the National Institutes of Health (NIH). The law states that sponsors must submit a certification of compliance with section 402(j) of the PHS Act for certain applications to the FDA that fall under Sections 505, 515, 520(m), 510(k), or 351 of the Federal Food, Drug, and Cosmetic Act.

Rationale: Sponsors who submit applications to the FDA for approval need to understand when they should submit an accompanying certification with the application. The FDA drafted this guidance to clarify which application types require the certification and which ones may be exempt from certification. In addition, FDA explained how it enforces this recent amendment to the PHS Act.

Summary: Since the implementation of FDAAA, sponsors marketing a drug product, biological product, or a medical device have had to provide information related to their clinical trials so the public could access such information from the clinical trial data bank. However, this amendment has expanded the scope of clinical trial information that sponsors must provide to the FDA and certify that the information collected is done in accordance with 42 USC §282(j)(5)(B), Section 402(j) of the PHS Act.

Resulting Recommendations: An applicant must submit the certification when submitting the following application types:
• New Drug Application (NDA)
• Biologics License Application (BLA)
• Premarket Approval (PMA)
• Humanitarian Device Exemption (HDE)
• Efficacy Supplement to approved NDA or BLA
• Abbreviated New Drug Application (ANDA)
• PMA Panel Track Supplement
• Investigational New Drug Application (IND)
• 510(k) pertaining to a clinical trial
• New Clinical Protocol Submitted to an IND
• Any resubmission of the aforementioned categories

Applicants demonstrate that they have complied with the requirements of 42 USC §282(j)(5)(B) by submitting the FDA form, 3674 Certification of Compliance, under 42 USC §282(j)(5)(B), with Requirements of ClinicalTrials.gov Data Bank (42USC § 282j), (http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048364.pdf).

The FDA uses judgment when considering other types of submissions. For example, if a supplement to an approved application does not refer to a clinical trial, or refers to one already certified in the previously approved application, then certification is not necessary. The same applies to a 510(k) application that does not include information related to a clinical trial. Lastly, an IND that does not include a controlled clinical trial and falls under 21 USC § 360bbb does not require certification.

Impact: Under this amendment, sponsors have a greater burden to demonstrate transparency to the FDA, NIH, and most importantly, the public. FDA will have greater responsibility in enforcing compliance with this amendment and communicating information to NIH. The guidance is clear as to what types of applications/submissions require the certification, which should reduce the likelihood of prohibited acts (eg, forgetting to submit the certification when required, not providing clinical trial information when required) and monetary fines for sponsors.

CMC Analytical Procedures and Methods Validation

Guidance for Industry: Analytical Procedures and Methods Validation—Chemistry, Manufacturing, and Controls Documentation

This draft guidance was released in August 2000 and is available at http://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

Guidance for Industry: Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply

Name: Recommendations for the Assessment of Blood Donor Suitability, Blood Product Safety, and Preservation of the Blood Supply in Response to Pandemic (H1N1) 2009 Virus [Docket No. FDA-2009-D-0533]

Status of Guidance: Draft Guidance

Guidance Released: November 13, 2009

Due Date for Comments on Guidance: December 3, 2009. Although anyone may comment on any guidance at any time [see 21 CFR 10.115(g)(5)], to ensure that the agency considers comments on this draft guidance before beginning work on the final version of the guidance, written or electronic comments on the draft guidance were due by December 3, 2009.

Link to Draft Guidance: http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/UCM190373.pdf
Link to Comments on Draft Guidance: http://www.pptaglobal.org/UserFiles/file/FDAA09015_FINAL.pdf

http://www.aabb.org/Content/News_and_Media/Comments/comments120309.htm

Target Audience: Blood establishments. Blood establishments are those facilities that manufacture whole blood and blood components intended for use in transfusion as well as whole blood and blood components that are intended for further handling, including the components of recovered plasma, source plasma, and source leukocytes.

Definition Terms Used in the Target Audience Section: Whole blood is a general description for a sample of blood drawn from a person’s vein or artery. Whole blood is composed of red blood cells, white blood cells, platelets (thrombocytes), and plasma. White blood cells are also called leukocytes of which there are several types, namely, granulocytes (neutrophils, eosinophils, and basophils), lymphocytes, and monocytes. Plasma is the pale yellow watery fluid of the blood that contains no cells, but in which the red cells, white cells, and platelets are suspended. Red cells, white cells, platelets, and plasma are blood components. Recovered plasma is plasma pooled from whole blood donations. Source plasma is plasma obtained directly from a donor by a process known as plasmapheresis in which the donor’s plasma is removed and his/her red cells, white cells, and platelets are returned to his/her circulation. Source leukocytes are white blood cells obtained directly from a donor by plasmapheresis in which the donor’s leukocytes are removed and his/her plasma, red cells, and platelets are returned to his/her circulation.

Laws and Regulations Referenced:

1. Section 319 of the Public Health Service Act, 42 U.S.C. § 247d grants the Secretary of Health and Human Services (HHS) broad authority to determine that a public health emergency exists.

2. 21 CFR 211.25 Personnel qualifications.

3. 21 CFR 601.12(c)(5) Biologics licensing; Changes to an approved application.

4. 21 CFR 606.20 Training of personnel.

5. 21 CFR 606.170(b) Reporting of blood donor and blood recipient fatalities.

6. 21 CFR 606.171 Reporting of product deviations by licensed manufacturers, unlicensed registered blood establishments, and transfusion services.

7. 21 CFR 640.3(a), (b)(1) and (4) Suitability of whole blood donors.

8. 21 CFR 640.63(a), (c)(1) and (7) Suitability of source plasma donors.

Summary:
This guidance provides US Food and Drug Administration (FDA) recommendations for assessing the suitability of blood donors, assessing blood product safety, and preserving the blood supply in reference to the 2009 pandemic (H1N1) influenza virus.

Rationale: Although the potential for transmission of the 2009 pandemic (H1N1) influenza virus by blood transfusion remains unknown, because of the known potential for this virus to spread rapidly, H1N1 infection has the potential to cause disruptions in the blood supply. Therefore, recommendations regarding how to assess the suitability of blood donors, how to assess the safety of blood products, and how to preserve the blood supply during this pandemic are necessary.

Resulting Recommendations: The first recommendation addresses the training of back-up personnel. Blood establishments are required by 21 CFR 211.25 and 21 CFR 606.20 to have an adequate number of employees to perform necessary tasks, and to ensure that all personnel possess the proper educational background, training and experience to assure competent performance of their assigned functions. The FDA recommends that blood establishments have adequate back-up personnel in the event of anticipatable personnel shortages as the result of disease caused by the2009 pandemic (H1N1) influenza virus.

The second set of recommendations addresses three issues: blood donor suitability, blood donor deferral, and blood product management. With regard to blood donor suitability, the FDA recommends that, because a blood donor’s responses to the donor questions presented before blood collection are occasionally found to be incomplete, blood establishments may obtain omitted responses to questions within 24 hours of the blood collection.

Regarding the deferral of blood donors, to ensure donors are in good health on the day of blood donation as required under 21 CFR 640.3(b) and 21 CFR 640.63(c), blood donors with a confirmed or probable case of pandemic (H1N1) 2009 virus infection should be deferred until at least 24 hours after they are free of fever without the use of fever reducing medications (a daily dose of pediatric aspirin [81 mg] is not considered fever-reducing medication) and they are otherwise asymptomatic. Additionally, data do not support deferring blood donors after vaccination with live attenuated influenza vaccines or inactivated influenza vaccines against pandemic (H1N1) 2009 virus or for prophylactic use of the antiviral medications oseltamivir (Tamiflu) and zanamivir (Relenza). However, to be consistent with the recommendation regarding blood donors who were infected with probable pandemic (H1N1) 2009 virus, blood donors taking antiviral medications for confirmed or probable pandemic (H1N1) 2009 virus infection should be deferred until at least 24 hours after they are free of fever without the use of fever reducing medications and they are otherwise asymptomatic.

The FDA’s recommendation on blood product management applies to donations of whole blood and blood components intended for transfusion. This recommendation does not apply to blood components intended for further manufacture such as recovered plasma, source plasma, and source leukocytes. The reason for this is that validation studies have shown that viruses with similar characteristics to 2009 pandemic (H1N1) influenza virus (a large lipid-enveloped virus) are effectively inactivated and/or removed during the manufacture of plasma derivatives. The FDA recommends that upon receipt of post donation information about a donor with confirmed or probable pandemic (H1N1) 2009 disease or influenza like illness within 48 hours after the donation, the Medical Director evaluate the safety of the donations from that donor consistent with existing Standard Operating Procedures.

The final recommendation addresses changes to approved applications from licensed blood establishments. The FDA recommends that the change of using a different outside testing laboratory may be submitted as a “Supplement-Changes Being Effected”. Also, the FDA recommends that the change of implementing self-administered donor history questionnaires may be submitted as a “Supplement-Changes Being Effected”.

In this guidance, the FDA also reminds blood establishments that if a complication of a blood transfusion results in the death of a blood recipient, then the blood establishment must report the fatality to the FDA as soon as possible. The last FDA reminder to blood establishments concerns convalescent plasma which is plasma obtained after recovery from an acute infection. In theory, the transfusion of convalescent plasma might be used as empirical treatment during an influenza pandemic. However, because of its experimental nature, collection and administration of convalescent plasma should be conducted only under an Investigational New Drug Application (IND). The FDA recommends that blood establishments that intend to manufacture convalescent plasma should contact the FDA to discuss their plans.

Impact: The goal of this recommendation is to ensure that the blood supply in the US is maintained at an adequate level and that the blood and blood products are kept free of the 2009 pandemic (H1N1) influenza virus so that this virus is not spread from person to person by the administration of blood and blood products. Patients who need blood transfusions most likely have serious health problems. The most severe outcomes of infection with 2009 pandemic (H1N1) influenza virus have been reported among individuals with underlying health problems that are associated with a high risk of complications from influenza. These severe outcomes can be avoided by maintaining a blood supply that is free of 2009 pandemic (H1N1) influenza virus.

Blogger’s 2¢: I found two sets of comments on this guidance. The first is dated December 3, 2009, and is from the American Association of Blood Banks (AABB). The AABB suggests three changes to this draft guidance. First the AABB comments that obtaining a donor’s omitted responses to questions within 24 hours of the collection should be made explicit not only for the 2009 pandemic (H1N1) influenza virus because it is applicable to assessments of blood donor suitability/eligibility in general. Second and third, the AABB suggests that two of the recommendations not be restricted to use in a pandemic. Namely, the fact that the change to a different outside test lab and the change of implementing a self-administered donor history questionnaire are now recommended to be submitted as a “Supplement-Changes Being Effected” should apply at all times, not just during a pandemic.

The second set of comments is also dated December 3, 2009, and is from the Plasma Protein Therapeutics Association (PPTA). The PPTA is the international trade association and standards-setting organization for the world’s major producers of plasma-derived and recombinant analog therapies. The PPTA also suggests three changes to this guidance. First, regarding the training of back-up personnel in blood establishments, the PPTA recommends that the following line be deleted, “more than one back-up personnel should be trained for each critical function” because the number of people trained for one function is not important as long as blood establishments take reasonable steps to assure continued operations during a pandemic. Second, regarding blood donor suitability, the PPTA would like the following statement deleted or further clarified to include interpretive criteria to prevent the needless destruction of life-saving blood components, “You may clarify a donor’s response to the donor history questionnaire or obtain omitted response to questions within 24 hours of the collection.” Third, with regard to the collection and use of convalescent plasma, the PPTA agrees that the administration of convalescent plasma should be conducted only under an IND; however, the PPTA disagrees that simply the collection of convalescent plasma must also be performed under an IND.

It will be interesting to see how the FDA includes the comments from the AABB and PPTA in the final guidance. If I become aware of the final guidance before the end of this semester, I will post a link to it on this blog.

Kent’s #2 Blog Post: Safety Testing of Drug Metabolites

Name of Guidance
Guidance for Industry: Safety Testing of Drug Metabolites

Status of Guidance
Final

Release Date
February 2008

Link to Guidance
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf

Target Audience
Drug trial sponsors, contract research organizations, and individuals charged with designing non-clinical safety evaluations and clinical safety evaluations

Laws and Regulations Referenced
Code of Federal Regulations (21 CFR part 58) Good Laboratory Practices

ICH Guidance for Industry M3 (R1) Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals

ICH Guidance for Industry S2A Guidance on Specific Aspects of Regulatory Genotoxicity Tests for Pharmaceuticals

ICH Guidance for Industry S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals

ICH Guidance for Industry S5 (R2) Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male Fertility

Summary and Rationale
Generally in drug development, metabolites have not been evaluated during non-clinical safety trials. However, sometimes clinically relevant, and possibly toxic, metabolites are not formed in animals but are formed in humans. Or certain metabolites are formed in higher concentrations in human plasma than in that of animals. Unfortunately in these cases, not until clinical trials do researchers identify metabolites’ contribution to the toxicity of the drug. As a result the toxicity profile of the drug in humans, clinical trials can be halted and time lost in drug development. To avoid this, metabolites should be identified as soon as possible during drug development. In this final guidance, the FDA recommends safety testing for metabolites, both in vitro and in vivo, during the non-clinical period.

Resulting Recommendations
The FDA encourages metabolite identification as soon as possible during drug development. In vitro studies can be performed using liver cells and slices from humans and animals. Later, in vivo tests can be used to determine whether the drug has the same metabolite profile in both animals and humans. Once the metabolites have been identified, toxicity, embryo-fetal development and carcinogenicity studies of the metabolites should be performed as soon as possible. During the clinical safety testing process, metabolite identification should be done as early as possible, as well. The toxicity studies should be performed according to ICH guidances for industry and good laboratory practice guidelines.

Impact
Sponsors developing new drugs will need to plan the non-clinical phases to include metabolite identification and toxicity testing on the identified metabolites. They will also need to allow enough time for testing and analyzing the results of their tests before moving on to the clinical phases of the drug development process. The FDA guidance will surely add more time to the pre-clinical process, but it can later save time if identifying possibly toxic metabolites saves research teams from having to stop clinical trials after recruitment.

Guidance for Industry: Postmarketing Studies and Clinical Trials -- Implementation of Section 505(o) of the Federal Food, Drug, and Cosmetic Act

This draft guidance was released in July 2009 at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM172001.pdf for applicants of new prescription drugs or biological products.

Laws and regulations referenced:

Authorization for the FDA to require certain postmarketing studies and clincial trials for prescription drugs including biological products approved under the new section 505(0) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(0)), which was added by section 901 of the Food and Drug Administration Amendments Act of 2007, or under section 351 of the Public Health Service Act (PHS Act, 42 U.S.C. 262).

Rationale: The new section 505(0) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(0)) authorizes the FDA to require postmarketing studies or clinical trials to access a known/potential new serious risk associated with a prescription drug or biological product at or after approval if the FDA aware of such a risk. Under the same section, applicants required to conduct postmarketing studies or clinical trials must also provide periodic status reports with specific required information on these studies, trials, or any other studies or trials undertaken to investigate a safety issue.

Summary: This guidance describes the requirements for postmarketing studies and clinical trials under 21 U.S.C. 355(0) and the types of postmarketing studies and clinical trials that will generally either be

• 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 under section 505(k)(1) and the new pharmacovigilance system to be established under section 505(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.

Linda's Blog #2 Establishment and Operation of Clinical Trial Data Monitoring Committees

Name of the Guidance:
Guidance for Clinical Trial Sponsors – Establishment and Operation of Clinical Trial Data Monitoring Committees
Status of the Guidance:
This guidance document is final.
When the Guidance was Released:
The guidance was finalized in March 2006. The draft guidance was distributed for comment in November 2001.
Link to the Guidance:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126578.pdf
Target Audience:
This guidance is targeted to sponsors of clinical trials for drugs, biologics, and medical devices, or to any contract research organization that has been delegated these responsibilities.
Laws and Regulations Referenced:
The regulations referenced in the guidance relate to the monitoring of clinical trials; 21 CFR 312.50 and 21 CFR 312.56 (for drugs and biologics) and 21 CFR 812.40 and 21 CFR 812.46 (for devices). The FDA mandates the use of an independent data monitoring committee only for clinical trials that are conducted in emergency settings where the requirement for informed consent has been waived (21 CFR 50.24).
Summary:
This guidance outlines the agencies current thinking on the creation and operation of Data Monitoring Committees (DMCs). A DMC is a formal committee made up of individuals who are independent from the sponsor of the clinical trial and who have relevant experience and expertise to monitor the progress of the trial on an ongoing basis. While the FDA recognizes that a DMC is not needed for most clinical trials, the agency does recommend that an independent DMC be formed for clinical trials with mortality or major morbidity as a primary endpoint, for trials that are large or lengthy, trials where the study population is vulnerable, or the where the study treatment has potential for serious outcomes or severe toxicity. The FDA does require the use of a DMC for clinical trials in emergency settings where the requirement for informed consent is waived.
The composition of the DMC is critical to ensure the committee is truly independent and adequately qualified for the data monitoring activities. When selecting members of the DMC the FDA recommends that the sponsors consider the level of each member’s expertise in the therapeutic area of interest and experience with clinical trials, and ensure that there are no conflicts of interest that would affect the DMC member’s decision-making ability. The FDA also recommends that the DMC operate under a written charter that includes standard operating procedures. It is recommended that the procedures cover the meeting schedule and format, requirements for recordkeeping, specifications for review of the data, process for review and protection of unblinded data, and requirements for reporting to the sponsor. Critical considerations when forming and operating a DMC include defining practical and applicable interim analysis time points, defining the statistical methods and type of data used for the interim analyses, and maintaining the integrity of the study blind.
Rationale:
A DMC is required by some government funding agencies, such as National Institute of Health for use in certain clinical trials; however, the FDA only requires the use of an independent safety monitoring committee for trials that will recruit subjects in emergency settings where the requirement for informed consent is waived. However, to improve the safety of study participants, this guidance recommends that sponsors consider using a DMC for large, multicenter trials that have mortality rates or major morbidity as primary endpoints or where there is a substantial risk to study participants. In order for the DMC to be effective, there must be standards for the appointment of committee members and the functioning of the committee.
Resulting Recommendations:
The FDA recommends the use of a DMC for large multicenter clinical trials where mortality rate or major morbidity is the primary endpoint or where the risk to study participants is significant.
Impact:
While the use of a DMC can substantially add to the administrative burden for a sponsor and can have an adverse impact on both trial timelines and budgets, independent monitoring of a clinical trial by a DMC can significantly increase the safety and welfare of research participants and improve scientific integrity of the clinical trial.

Kent’s #1 Blog Post: Xenotransplantation Products in Humans

Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of Xenotransplantation Products in Humans

Status of Guidance
Final Guidance

Released
April 2003

Link to Guidance
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Xenotransplantation/ucm074354.htm

Target audience
Sponsors of clinical trials as well as clinical investigators, source animal facility staff, and laboratory personnel involved in protocol development and regulatory submissions to the Food and Drug Administration (FDA), such as Investigational New Drug Applications (IND) and Biologics License Applications (BLA).

Laws and Regulations Referenced
Code of Federal Regulations Title 21 (21 CFR Part 312) regulates INDs for drugs and biologics for human use.

Public Health Services Act (42 U.S.C. 262), section 351, regulates xenotransplantation products, including cellular therapies, as biologic products.

Code of Federal Regulations (21 CFR Part 812) regulates investigational device exemptions (IDE) for xenotransplantation products that are a combination of medical devices biologic material.

Code of Federal Regulations (21 CFR Part 3) regulates combination products and assignment for premarket review of them.

Summary
A shortage of transplantation material from humans, such as hearts, kidneys and tissue from the pancreas, has lead researchers to consider using material from non-human animals for transplantation and implantation in humans. This process is called xenotransplantation. However transplanting tissues, organs, and cells from animals comes with risk of infection from viruses, bacteria, and other infectious agents from the animal donor to the human recipient. The final guidance addresses safety, clinical, and practical issues related to the production, testing, and evaluation of non-human animal material to be transplanted into humans. The goal of the guidance is to suggest methods that improve the safety of patients and researchers before, during, and after clinical trials involving xenotransplantation.

Rationale
Using animal-derived material in clinical trials presents a risk of transmission of disease from the donor animal to the human subject. Animals with some diseases do not show symptoms of the disease. In the worst cases, some diseases cannot be detected in the host animal without rigorous testing. In order to improve safety during clinical trials using animal-derived material, the animal’s provenance should be well documented and the animal material should be tested for a variety of pathogens, parasites, and diseases such as porcine endogenous retrovirus (PERV).

Resulting Recommendations
In order to improve safety, animal sources should be well documented and from US-based herds that are all from the same farm. The animals should be well supervised and not raised as free-range animals. Tissue should not come from slaughterhouses, either. At the time that material is harvested from the animal, samples should be archived for later testing, if necessary.

All xenotransplantation products should be tested for safety, identity, purity, and potency. Assay tests should be performed for bacteria, fungi, microplasma, viruses, and endotoxins. In cases where infectious agents are found, they should be inactivated or removed, or the animal material should not be used and should be disposed of properly.

When the product to be used in a clinical trial is a combination of animal material and medical device, the product should be tested preclinically for bioreactivity and biocompatibility.

Impact
When designing clinical trials using animal-derived material, sponsors and individuals involved in developing protocols should address where animal-derived material comes from, how it is tested for infectious agents, and how the safety of clinical trial subjects, laboratory personnel, and healthcare workers will be ensured.

Tracey's Blog: Guidance for Industry Development and Use of Risk Minimization Action Plans (RiskMAP)

This guidance was released as a final guidance in March 2005. It can be found online at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126830.pdf

TARGET AUDIENCE

The sponsor, usually a pharmaceutical company who develops prescription drugs, including biological drug products.

FDA LAWS AND REGUALTIONS REFERENCED

• 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!

Blog 1

Name of Guidance: E2B(R) Revision of the ICH Guideline on Clinical Safety Data Management: Data Elements for Transmission of Individual Case Safety Reports

Status of Guidance: Draft Guidance

When was the Guidance released?
This guideline was originally signed off July 17, 1997 and modified as E2B(M) guideline in November 2000. The E2B(R) was released 12 May 2005.

Link to the Guidance http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073096.pdf

Target audience: pharmaceutical companies, regulatory authorities, ethics committees

Laws and Regulations Referenced (and what each law states in relevant part}
World Health Organization – Collaborating Center for International Drug Monitoring
ICH E2A and E2D guidelines for life-threatening and other medically important conditions

Summary
This guidance objective is to standardize data elements for transmission of individual safety reports, by identifying and defining elements for the transmission of all individual safety reports, regardless of source and destination. This guidance includes the standards for data elements of safety reports for both pre and post approval periods and covers adverse drug reaction and adverse event reports.

Rationale
To standardize safety reporting.

Resulting Recommendations
This guidance will be followed for all safety reporting.

Impact
Clarifies reporting format
Provides standards for data transmission format
This standard allows for information to be transmitted in an encoded format.

Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials

Name: Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials


Status of Guidance: Final Guidance

Guidance Released: September 2007

Link to Guidance:
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/ucm074775.htm#TableofContents

Target Audience: Sponsors (eg, pharmaceutical companies), monitors (eg, clinical research associates), investigators (eg, research physicians), and Institutional Review Boards (IRBs) of vaccine trials

Laws and Regulations Referenced:
1. Section 351 of the Public Health Service Act (42 U.S.C. 262) by which the Office
of Vaccines Research and Review, Center for Biologics Evaluation and Research,
regulates preventive vaccines
2. The Federal Food, Drug, and Cosmetic Act, eg, Title 21 Code of Federal Regulations (CFR) Parts 312, 600, and 601, which address investigational new drug applications (INDs) and biologics license applications (BLAs)
3. 21 CFR 312.32, 312.33, 312.50, 312.55, 312.56, 312.60, 312.62, 312.64, and 312.66 which present the regulations involved with the recording, monitoring, and reporting of adverse events (AEs) in clinical trials

Summary: The Office of Vaccines Research and Review (of the Center for Biologics Evaluation and Research [CBER] of the Food and Drug Administration [FDA] of the US Department of Health and Human Services [HHS]) follows established rules to control the study of preventive vaccines. Preventive vaccines are most often developed to prevent disease in healthy people. When healthy people are enrolled in clinical trials, there is a very low tolerance for risk of AEs for the volunteer. The vaccine’s benefits should greatly outweigh its risks of harming a healthy volunteer.

To consistently evaluate the risk of AEs that healthy adult and adolescent volunteers undergo in preventive vaccine clinical trials, recommendations for the assessment of the severity of clinical and laboratory abnormalities are presented. The authors of this guidance recommend that these appropriate and uniform criteria be incorporated into the vaccine’s investigational plan (study protocol), case report forms, and study reports. That said, they also recommend that the clinical and laboratory parameters being monitored be tailored to the needs of each study vaccine. By this they mean that additional parameters might be added in a clinical study of a vaccine based on one or more of the following: safety signals detected in pre-clinical toxicology studies, the theoretical possibility of the occurrence of certain AEs, or prior experience with a similar licensed vaccine.

Rationale: If all sponsors of vaccine trials use uniform criteria for categorizing toxicities in healthy volunteers, comparisons of safety data among groups within the same study and also between different studies will be improved.

Resulting Recommendations: The following criteria should be assessed in all preventive vaccine clinical trials conducted in healthy adult and adolescent volunteers:

· Clinical: vital signs, local (injection site) reactions, and general (systemic) reactions
· Laboratory: results of serum chemistry assays, whole blood hematology tests, and urinalysis

When these criteria are outside of the normal range of results, they should be graded either Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3) or Potentially Life Threatening (Grade 4) according to the measurements listed in the Tables for Clinical Abnormalities and Tables for Laboratory Abnormalities of the guidance.

Impact: The use of uniform AE/toxicity criteria to evaluate the safety of vaccines in healthy volunteers will enhance our current understanding of immunization safety by improving the comparability of vaccine safety data. If this guidance is followed, many will benefit, not least of which are the current and future vaccinees. Additionally, scientists, health officials, and healthcare providers who need to make scientifically sound decisions and who need to obtain, interpret, provide, and report information on immunization safety will benefit.

My comments:
Many vaccines are administered to neonates, infants, toddlers, and children. This guidance would become complete if it also addressed toxicity grading scales for these patient populations.

The addition of language describing Serious Adverse Events (SAEs) and providing a distinction from severe AEs would also be helpful. It is not clear to me whether the Grade 4 (Potentially Life Threatening) category would be equivalent to an SAE.

Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims

Guidance for Industry – Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf

In December 2009 the FDA finalized a new guidance for industry providing guidelines for the development and testing of instruments used for collecting, measuring, and assessing patient-reported outcomes (PRO) that support labeling and promotional claims. Specifically, the guideline is written to inform sponsors of how the FDA evaluates the PRO instruments developed for use in clinical trials and it outlines the FDA’s expectations of the evidence that must be submitted to verify the validity and reliability of the PRO instrument. It is the FDA’s position that a PRO instrument must be shown to be a credible measure of the claim being made. The draft guideline was initially published for public comment in February 2006.

PRO instruments are designed to capture the patients’ perspective on the effectiveness of the medical product or intervention for aspects that can only be reported by the patient. Questionnaires and diaries are examples of PRO instruments used in clinical trials. Sponsors must demonstrate that the PRO instruments used for the collection of patient-reported outcomes to support a claim of a treatment benefit have been tested and validated for both content and the design and are able to effectively measure the particular concept being tested. In selecting a PRO instrument the sponsor must evaluate whether the instrument is capable of measuring the concepts of interest in the target population. In making these evaluations, the content and design of the PRO instrument must be validated and tested to show that the results are reliable and reproducible and are able to detect change. General considerations for content and design include the type and number of questions to include, recall period (timeframe the patients are instructed to consider when answering the questions), response options (visual analog scale, Likert scale, pictorial scale, checklist), and scoring methods for items or domains.

The FDA recommends that sponsors apply the same design principles that are followed for other endpoint measures to the PRO endpoints. For example, sponsors are expected to establish procedures to ensure consistency (instructions for administration of questionnaires) and to develop methods to minimize unintentional unblinding and for handling missing data to minimize bias. The guidance also includes a section on statistical considerations for analyzing the data collected with the PRO instruments.

The impact of the guidance helps sponsor understand the expectations of the FDA for patient-reported outcome data when the data is used for labeling claims. Following the guidelines for the development of the PRO instruments provides a sponsor with greater assurances that the data collected will be acceptable to the FDA and can be used to support labeling claims.

The guidance references the FDA regulations related to record keeping, maintenance and access – 21 CFR Part 312 (for drugs and biologics) and 21 CFR Part 812 (for medical devices). Another key reference is 21 CFR Part 11 defining the regulatory requirements for use of computerized systems. When creating and using PRO instruments, sponsors must ensure the methods of collecting data are in compliance with these regulations.

Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification on What to Report

Name: Postmarketing Adverse Experience Reporting for Human Drug and Licensed Biological Products: Clarification on What to Report

Status: final

Release date: August 1997

Link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071981.pdf

Target audience:

Industry required to report adverse experiences to the Food and Drug Administration, including

• Applicants of approved new drug applications, abbreviated new drug applications, and antibiotic applications
• Manufacturers (including packers and distributors) of marketed prescription drugs for humans
• Licensed manufacturers of approved biologic license applications

Laws and Regulations Referenced:

Revoking of the postmarketing safety reporting requirement to submit expedited increased frequency reports for human drugs and licensed biological products:

• Final rule in the Federal Register (62 FR 34166; June 25, 1997)

Postmarketing adverse event reporting:

• Guideline for Postmarketing Reporting of Adverse Drug Experiences (March 1992)
• Guidelines for Adverse Experience Reporting for Licensed Biological Products (October 1993)

Data to be included in a safety report:

• Code of Federal Regulations, title 21, 310.305, 314.80, 314.98, and 600.80
• International Conference on Harmonisation (ICH) E2A document
• Guideline on Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (60 FR 11284; March 1, 1995)
• International Reporting of Adverse Drug Reactions, 1990: definition of Minimum Standard of Information
• International Reporting of Periodic Drug-Safety Update Summaries, 1992: definition of CIOMS Reportable Case histories (CIOMS Report)

Summary: This guidance provides recommendations to industry on how best to do postmarketing safety reporting, including what data must be gathered before an adverse experience should be submitted to the FDA and how to handle solicited safety information from patients. This guidance also encourages the use of waiver requests for periodic safety reports for adverse experiences that are classified "nonserious and labeled" (i.e., included in the labeling for marketed products) .

Rationale: More and more individual safety case reports are being submitted to the FDA without sufficient data for interpretation/evaluation. "Nonserious and labeled" adverse experiences are the fastest growing type of safety report to be submitted to the FDA. Guidance is needed to improve postmarketing safety reporting and to reduce the burden of safety reporting on industry without compromising public health.

Recommendations:

The four following criteria should be obtained for each safety report, and safety reports without all of the criteria should not be submitted

1. an identifiable patient (identified by an assigned code, not name or address; with specific information, e.g., "an elderly woman")
2. an identifiable reporter
3. a suspect drug/biological product
4. an adverse event (at minimum: specific signs [including abnormal laboratory values], symptoms, or disease diagnosis)/fatal outcome (reporting required even if the adverse event is unknown)

Potential adverse experiences from planned contacts and active solicitation of information from patients (e.g., sponsored patient support programs, disease management programs) should not be submitted to the FDA unless an adverse event is classified "serious and unexpected" (see definitions for "serious adverse drug experience" and "unexpected adverse drug experience" here) and is possibly reasonably related to the human drug or biological product.

Requests to waive reporting of "nonserious and labeled" postmarketing adverse experiences are encouraged for human drugs but not for new biological products within one year of approval or blood products, plasma derivatives, or vaccines.

Impact: Submission of postmarketing safety reports with insufficient data (e.g., "some patients had anaphylaxis") and nonserious and known adverse events will be reduced. This will decrease the burden of safety reporting on industry and consequently decrease the corresponding workload of the FDA reviewers. With fewer and cleaner safety reports for the FDA to review, new and significant safety signals may be identified faster.

Tracey Blog: Guidance for Industry: Acceptance of Foreign Clinical Studies

The Guidance for Industry: Acceptance of Foreign Clinical Studies was released as a final guidance in March 2001. This guidance can be found online at http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm124939.pdf.

Target Audience:

The sponsor (financial supporter, often a pharmaceutical company) of a clinical trial

Laws and Regulations Referenced:

• Title 21 of the Code of Federal Regulations, part 312 (Investigational New Drug Application [IND]); referred to as 21 CFR Part 312.
• Title 21 of the Code of Federal Regulations, part 812 (Investigational Device Exemptions [IDE]); referred to as 21 CFR Part 812.
• Title 21 of the Code of Federal Regulations Part 814 (Premarket Approval of Medical Devices)

Rationale:

In the United States prior to testing new drugs or devices on humans the FDA requires sponsors to complete an Investigational New Drug Application (IND) for drugs or an Investigational Device Exemption (IDE) for a medical device. The regulations for clinical studies conducted under an IND or IDE, including ethical standards the FDA expects to be followed during the conduct of these clinical trials, are described in Title 21 CFR Part 312 and Part 812, respectively.

In general, the international medical community adheres to the ethical principles outlined in the Declaration of Helsinki. This declaration was originally adopted by the World Medical Association’s in 1964 and has since been revised 5 times. With each new version the FDA assesses the changes and decides whether the relevant regulations should be updated. At this time, the regulation for INDs (21 CFR Part 312) incorporates language from the 1989 version of the declaration; the regulation for IDEs (21 CFR Part 814 incorporates the 1983 version of the Declaration of Helsinki.

Studies conducted outside the United States may or may not be conducted under an IND or IDE. The FDA has written Guidance for Industry: Acceptance of Foreign Clinical Studies to provide their expectations with regards to the ethical treatment of people participating in clinical studies conducted in countries other than the United States.

Recommendations:

Foreign studies conducted under and IND or IDE must comply with the same regulations as those conducted in the United States. However, the FDA will also accept foreign studies that were not conducted under an IND if they adhere to the ethical standards outlined in the 1989 version of the Declaration of Helsinki. Studies conducted under an IDE will be accepted if they adhere to the ethical standards outlined in the 1983 version of the Declaration of Helsinki. Both types of studies will be accepted by the FDA if they were conducted using the ethical principles of local regulatory authorities if their principles provided greater participant protection than the declaration.

Impact:

As more clinical trials are being conducted the competition for study participants is also increasing. In addition, research is being conducted on diseases that do not occur in this country. In these cases clinical studies may be conducted in the location where the disease is found. As a result, sponsors are going into countries where there may be little or no oversight regarding the ethical treatment of study participants. Therefore, this guideline is essential. Although most sponsors of drugs and devices are ethical, for those who might be motivated by money to cut corners that might but study participants at risk, the FDA is forcing them to put people first. With this guidance the FDA is making a statement: follow the guidelines or risk spending a lot of money on data that cannot be used to support approval of a drug or medical device.