Informed consent regulations are in Part 50. The scope of the rule covers all clinical investigations including foods and dietary supplements bearing a health claim, infant formulas, food additives, drugs, medical devices, biological products, and electronic products. Part 50 also covers informed consent, which has basic elements and additional elements. The additional elements include: unforeseeable risks to the subject, or, as applicable, the subject’s fetus or embryo; whether and how the investigator may terminate the study without the subject’s consent; additional costs for which the subject may be responsible during the course of the study (for example, transportation to the clinic, or parking on at the research facility, copying, and mailing study-related medical records); the consequences of withdrawing from the research protocol (for example, possible rebound of skin disease if a study drug is abruptly discontinued), and the procedures for withdrawal; a statement that new findings related to the study drug may be made available to the subject as they become known (for example, if a drug is vastly superior to placebo in a melanoma trial, the trial may be halted as further delivery of placebo may be considered unethical; and the approximate number of subjects in a study. The informed consent will also contain the following statement, as required by law:
“A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”
In the case of studies involving children, no additional IRB requirements are necessary as long as the risks to children are minimal, and adequate provisions are made for soliciting the child’s assent and the parent or guardian’s consent. If the risk to children is greater than minimal, the IRB can only approve a study if the (a) the benefits justify the risks, (b) the benefit is at least as great as that offered by already available alternatives, and (c) adequate provisions are made for soliciting the child’s assent and the parent or guardian’s consent. In studies where the risk is greater than minimal, and no direct benefit to the volunteer is provided other than providing generalizable knowledge, the IRB must show that the added risk is only a small increment above minimal risk and that the knowledge obtained is vital for improving or understanding the subject’s condition. For conditions not meeting the above criteria, but which the IRB or sponsor feel merit consideration for study, the petition must demonstrate that the study offers (a) a reasonable potential of understanding or improving a serious condition which affects the health or welfare of children, (b) the Commissioner of Food and Drugs consults with a panel comprised of appropriate experts (for example law, medicine, education, ethics, science) and allows a period of public commentary which confirms the sponsor’s stance, and which is conducted according to solid ethical principles.
12.2 Audits
Audits are common, and even more common if you are a successful investigator with a successful study. Often, the FDA will audit sites which are ‘high enrollers’ in studies. One of the best ways to be ready for an FDA audit or inspection is to be prepared. You will get little notice, typically 1 week, to get ready, and unless you are away because of illness or a long-planned vacation, accept the appointment day granted by the agency. Delaying the inspection will be granted, but, unless it’s for a good reason, is likely to earn you even more scrutiny.
Preparation for audits begins long before they ever occur. As an investigator or research site, you and your staff need to understand the requirements of the FDA for studies. You need to make sure you have all of your documentation in order. You need to have internal policies and procedures for ensuring the quality, integrity, and validity of your data, and the health, welfare, and safety of your research subjects. You need to make sure your protocols are carefully followed, and that any deviations or violations are carefully documented, and addressed. You need to take advantage of your sponsor oversight to ensure that you are following the protocol. You need to listen to your monitor during your studies. You also need to make sure your training and certifications are valid and up-to-date. As part of your training, you may wish to hold periodic mock-FDA audits to prepare yourself and your staff.
When you learn of an audit, notify your sponsor immediately. Some sponsor agreements require it, and some sponsors have the resources to help you deal with the administrative burdens of an audit. It is in the sponsor’s best interest to have you emerge successfully from an audit so that the data you have worked so hard to deliver, and they have paid so much to collect, remains valid and usable in a drug or device application.
You also should get familiar with FDA procedures, so that you can be prepared for the types of questions, and inquiries you will face. It will give you confidence during the visit to address any scenario that might arise. Plan on getting an experienced, thorough, and poker-faced agency officer visiting your site. This will ensure that you are overprepared.
The results of audits can be hard to predict, and factor in many possibilities, including sidelines of inquiry by a curious agency inspector and fishing expeditions if you or your staff get off tangent. This should not happen if you are prepared and answer only the questions you are asked. However, it is good to have someone taking notes while the auditor is at your site. The notes should include dialogue, and observations on what the inspector is doing and where he or she is going. This way, you will be able to corroborate or challenge the details of any finding or report submitted by the agency. A good note taker is someone familiar with audits and the policies and procedures of clinical trials in general and your site in particular.
Have one person designated to be assigned to the auditor. This person should be the primary contact for the auditor and escort him or her throughout your facility.
Some of the documents you will need for the auditor include an information brochure about your organization, including an overview of your research site, an organizational chart, and any complaints about your site. Have all your documents ready, and be sure that your facility is in top shape for inspection.
It is good to prepare your staff for questions the auditor might ask. Questions typically revolve around company policies, the job description of each employee including their duties, training, and qualifications. There may be questions about errors, and policies and procedures for handling errors. Be sure your staff knows how to answer these questions with the most current and accurate information. If they don’t know an answer, be sure they admit it, and offer to research answers and get back to the inspector as soon as possible.
Be sure your most diligent staff are around on the day of the inspection. The auditor may not speak with everyone, but will likely be observing the activities and processes of your facility during the course of the inspection. If feasible, problem workers and inexperienced workers should not be on duty on the day of the inspection.
Auditors want to make sure that your study was done according to the protocol and FDA guidelines. They have a checklist that they go through. Knowing this checklist will help you prepare for an inspection.
1.
They want to be certain that the data are of high quality, valid, and collected properly.
2.
They want to make sure human subjects were protected.
3.
They want to know that the sponsor, CRO, PI, and site adhered to all regulations, guidelines, GCPs and the final version of the IRB approved protocol.
4.
Types of audits:
a.
Audits can be for bioequivalence studies, where only one study is the basis for approving an equivalent pharmaceutical.
b.
Routine audits are typically for studies such as primary efficacy studies, and studies submitted for marketing, licenses, or NDAs.
c.
For cause audits, because there is a concern expressed about a particular investigator.
Study-related audits typically involve randomly selected study sites. Occasionally sites that meet certain criteria are selected as well. These can include sites which have high enrollment, sites which enroll subjects very rapidly, sites which conduct numerous studies simultaneously, sites which conduct pivotal trials on which the majority of the IP’s claims are based, and sites which switch a pharmaceutical or device from prescription to OTC status. Many times, sponsors can predict if your site is likely to be audited.
For cause inspections occur under a number of circumstances. An investigator may be selected for inspection if he or she conducts many studies outside his or her specialty. If an investigator conducts a pivotal study for NDA or a license, he or she may be audited. If the investigator submits safety and efficacy data which depart significantly from other sites under the IND/IDE, there may be an inspection. If the sponsor notifies the FDA or the subject complains to the FDA, the site may be investigated. If a study garners a lot of extra media attention, it may be audited. If there is a larger number of subjects than would be predicted with a specific diagnosis, an audit may be triggered. For example, if you are doing a study of a rare genodermatosis, and are in a small town, and recruit several-fold more subjects for your study than sites in large metropolitan areas, you may be subject to an investigator-related audit.
You will be notified, and your sponsor will be notified in writing with a Notice of Inspection on FDA Form 482. The agency will request a meeting at a reasonable time that is mutually convenient. You are typically given a few days to a few weeks advance notice. Respect the agency’s time frame. If you delay more than ten days without a very good cause, you will only raise suspicion and more intense scrutiny. The FDA may request an audit any time, even many years after a study has been completed. Neither you nor your sponsor may legally refuse access to your files to the FDA.
As soon as you become aware of an FDA audit, notify your sponsor and the IRB. The FDA may also inspect the IRB related to the study if it has not been inspected in the past 5 years. Depending on the complexity of the study, the size of your site, and other factors, an audit may last 3–5 days.
As an investigator, familiarize yourself with the study. Review the protocol in detail, including the consent, inclusion and exclusion criteria. Review the data, including protocol deviations and violations, adverse events, and any situation where there was a complaint, or an issue regarding the health, safety or welfare of subjects. Review your SOPs and be sure you followed SOPs and GCPs in addressing any concern and that you documented your findings and any corrective actions clearly and thoroughly.
Be familiar with your staff and the staff who worked on the study. Some of the staff may have left or retired, particularly if the audit occurs years after a study closeout. Review your study documents and make sure they are all readily accessible, organized, and complete. As you review the documents, ask if they verify drug or device accountability, and compliance with regulations (including an updated FDA 1571/1572, IRB review and IRB approval, IND safety reports, current Investigator’s Brochure, current Protocol, financial disclosures, and all communication with the sponsor and the FDA). Be sure that you and your staff have the proper documents certifying your credentials (medical licensure, CLIA licensure, DEA licensure, in-house training, CVs current over the past 2 years, and any additional training—for example, GCP training, CITI training). Other important study documents which show protocol compliance are legible and accurate CRFs and source documents. Be sure these documents explain any deviations or violations, any adverse or unanticipated events, and any appropriate follow-up.
Inspectors use these documents to verify the existence of subjects, their eligibility for enrollment (through source documents like medical records, clinic visit notes, shadow charts, lab results, imaging results, prescriptions, signed informed consent). Inspectors want to verify that the informed consent was gathered according to regulations and was signed before participation in the study.
You should have at hand all the documents the inspector needs. However, you should ask the inspector what documents they require. Each site, inspector, and case is different. They will know if they are there to address only specific questions or do a more comprehensive inspection. The FDA follows a guidance manual which is available online. You can read it to see the inspector’s checklist: http://www.fda.gov/ICECI/EnforcementActions/BioresearchMonitoring/ucm133562.htm.
Set aside a space for the inspector that is comfortable, clean, and free of distraction. Do not offer amenities such as coffee, donuts, lunch or anything that could be misconstrued as unduly influencing the inspector. Take documents to this area as they are requested by the inspector. Be sure that you and your staff are available if called by the inspector. Do not leave the inspector unaccompanied. Be sure the inspector has access to a photocopy machine.
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