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FDA gives guidance to sponsor-investigators

Friday, January 15, 2016

Last May FDA released a draft guidance designed to assist sponsor-investigators in preparing and submitting complete investigational new drug applications (INDs) to FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER).1 “Sponsor-investigators seeking to do clinical research often do not have the regulatory knowledge or the resources to hire experts to help them with the IND submission process,” the draft guidance says. This guidance is not an exhaustive step-by-step instruction manual but rather a document that “highlights certain elements of this process to facilitate a sponsor-investigator’s successful submission of an IND.” The guidance also discusses the IND review process and general responsibilities of sponsor-investigators related to clinical investigations.

The draft guidance defines a sponsor-investigator as an individual who “both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.” The term, as defined in FDA regulations, does not include any entity other than an individual. “As the name suggests, a sponsor-investigator assumes the responsibilities of, and must comply with, FDA regulations applicable to both a sponsor and an investigator. These responsibilities include the submission and maintenance of an IND,” the draft guidance says.

What to include in the IND submissions

The information that the sponsor-investigator needs to include in the initial IND submissions falls within the broad categories listed below. (See section IV, Certain Information Required for an IND Submission, for additional details and 21 CFR 312.23 for a comprehensive list.) In some circumstances, FDA says, the sponsor-investigator will not need to include all of this information.

  • Sponsor-investigator information: Information on the qualifications of the sponsor-investigator who intends to conduct the clinical trial. “This information allows assessment of whether he or she is qualified to fulfill his or her clinical trial commitments,” the draft guidance says.
  • Investigator’s brochure (required of sponsors and recommended but not required of sponsor-investigators): A summary of the chemical, toxicological, and pharmacokinetic aspects of an investigational drug, including any information on its safety and efficacy obtained from any prior clinical trials, and a description of any anticipated risks, side effects, precautions, and special monitoring.
  • Clinical trial protocol: A detailed description of the intended investigation, depending on the drug development phase.
  • Chemistry, manufacturing, and control information: Sufficient information that ensures the proper identification, quality, purity, and strength of the investigational drug.
  • Pharmacology and toxicology information: A summary of nonclinical (in vitro or animal) data that is intended to support the safety of the proposed clinical trial.
  • Summary of previous human experience: If applicable, a summary of all clinical trial results intended to support the safety of the proposed clinical trial.

After the IND is sent

After FDA receives the IND, it will send an IND Acknowledgement Letter to the sponsor-investigator. The letter includes information such as the assigned review division, IND number, division contact, and the official FDA date of receipt. It is important to note that by regulation a proposed trial may not begin until 30 calendar days after the official FDA receipt. During this time the division’s multidisciplinary review team will review the proposed clinical trial materials. The review team includes clinical reviewers, chemists, toxicologists, clinical pharmacologists, and project managers. The team reviews the proposed investigational drug’s formulation, toxicity, nonclinical pharmacology and toxicology, and any previous human experience provided. The team may also consider other proprietary studies and clinical trials in similar drugs. In addition, it may perform literature searches.

The sponsor-investigator may or may not hear from FDA by the end of this 30-day review period. If the trial obtains IRB approval, it may proceed after the time period unless notified by the FDA that the trial is on clinical hold. The sponsor-investigator may also be notified promptly if FDA makes the determination that a trial that has been initiated needs to be suspended. This is further described in section VI.A. in the guidance, Clinical Holds and Requests for Modifications. Some of the reasons FDA may place a proposed or ongoing clinical trial on hold include:

  • Human subjects are or would be exposed to an unreasonable and significant risk of illness or injury.
  • The sponsor-investigator is not qualified, by reason of his or her scientific training and expertise, to conduct the trial.
  • The investigator’s brochure is misleading, erroneous, or incomplete (where applicable).
  • The IND contains insufficient information for the FDA to assess the risks to subjects of the proposed trial.
  • The IND is for the study of a drug intended to treat certain diseases or conditions and limits the eligibility of prospective subjects because of the risk or potential risk of reproductive toxicity.
  • For Phase 2 or 3 trials, the plan or protocol for the investigation is clearly deficient in design to meet its stated objectives.

According to the draft guidance, FDA may also place on clinical hold a proposed or ongoing trial that is not designed to be “adequate and well-controlled,” or if the criteria for a trial involving an exception from informed consent, as described in 21 CFR 50.24, are not met.

If FDA decides to place the trial on a clinical hold, it will send a letter within no more than 30 days to the sponsor-investigator that provides a written explanation of the basis for the hold. The letter may also describe the specific issues and deficiencies that led to the hold, what the sponsor-investigator must do for FDA to remove the clinical hold, and other comments. A sponsor-investigator may not proceed with this clinical trial until the sponsor-investigator has been notified by FDA that the hold has been lifted.

Be both sponsor and investigator

One of the most important statements in the draft guidance is that sponsor-investigators conducting trials under an IND must comply with both the sponsor and investigator responsibilities specified in 21 CFR parts 312, 50, and 56. Some of the responsibilities discussed in these regulations are below:

  • Good Clinical Practice, including human subject protection and IRB review and approval (§ 312.40, 21 CFR Parts 50 and 56). “In general, the sponsor-investigator should conduct trials according to good clinical practice (GCP),” the draft guidance says. Sponsor-investigators also must conduct trials in compliance with FDA regulations about the protection of human subjects and about IRB review and approval of studies.
  • Monitoring ongoing investigations. “We recommend that sponsor-investigators submit a brief summary to the IND to demonstrate that there is adequate monitoring of the clinical investigation to demonstrate the trial(s) are conducted in accordance with regulatory requirements, GCPs, and the protocol; that the rights and well-being of human subjects are protected; that data reporting, including safety reporting to the sponsor-investigator and the IRB, is accurate and complete; and that the sponsor-investigator has adequate oversight over the clinical investigation, as outlined in 21 CFR part 312, subpart D,” FDA says in the draft guidance.
  • Promotion of or charging for investigational drug (§§ 312.7, 312.8). Promoting the investigational drug is not permitted. Charging for the investigational drug is only permitted in rare circumstances, and then only with prior written approval by the FDA, the draft guidance says.
  • Records and reports (§§ 312.57, 312.58, 312.62, 312.68). A sponsor-investigator must maintain adequate and accurate case histories and must also maintain adequate records showing the receipt, shipment, or other disposition of the investigational drug, FDA says. The FDA may periodically check the trial site to make sure the critical data are being captured and stored. Sponsor-investigators are required to retain records and reports for “2 years after a marketing application is approved for a drug or, if an application is not approved for the drug, until 2 years after shipment and delivery of the drug for investigational use is discontinued and the FDA has been notified (21 CFR 312.57(c)).”
  • IND safety reports. A sponsor-investigator must review all information relevant to the safety of the investigational drug and notify FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than 7 calendar days after receipt of the information, FDA says in the draft guidance. The sponsor-investigator must also notify FDA in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualifies for reporting under § 312.32(c)(1)(i)756 (iv).
  • IND annual report (§ 312.33). Within 60 days of the anniversary date that an IND went into effect, a sponsor-investigator must submit a brief annual report of the progress of the trial. “The annual report is intended to update the review division as to all relevant developments over the preceding year,” the draft guidance says. The guidance also gives examples of the information that should be included in the IND annual report.

Get familiar with the process

Sponsor-investigators need to become familiar with this guidance, says Bart Cobert, a pharmacovigilance and drug safety consultant. “In my experience, both setting up IITs [investigator-initiated trials] and in doing audits of companies, there is often a woeful lack of understanding of the [sponsor-investigator’s] requirements and responsibilities,” he says on the website for C3i Healthcare Connections.2 “Many [sponsor-investigators], as well as some [contract research organizations], academic centers, and others in the U.S. and abroad, do not fully realize what they are getting into nor do they quite understand their legal responsibilities and potential liabilities. “

Cobert also believes there is still a large amount of looseness in place regarding IITs. Many companies and many academic centers do not have adequate standard operating procedures, rules, restrictions and oversight for them. “This can place patients, [sponsor-investigators], and companies at risk. If a non-approved indication is being studied, this trial should have oversight sufficient to protect the patients and all others involved. The section in this guidance on clinical holds indicates that FDA will certainly be monitoring these IITs. The company, the institution, the IRB, and all the other players involved must treat these trials as seriously as they treat any other IND clinical trial.”

The need for these trials

Even with the problems SIs encounter, IITs have a special purpose in the industry, says Viraj Suvarna in an article published in the journal Perspectives in Clinical Research.3 “Clinical trials are not, and cannot be, designed to determine all the potential uses for a medication. IITs expand product knowledge, including safety. Physician researchers often identify new ways of using existing treatments, thus improving the health of numerous other patients. And there is always greater weight attached to non-industry sources of data. Even large pivotal randomized clinical trials are done by academic research organizations, e.g., Public Health Research Institute (PHRI) or Duke Clinical Research Institute (DCRI),” says Suvarna, medical director at Boehringer Ingelheim India Private Limited, Mumbai, India.

“[The evidence from] gold standard prospective, randomized, double-blind, controlled clinical trials, while it may help prove the efficacy of the drug and garner marketing authorization approval, may need to be complemented by studies done by doctors in the real world,” she says. “The former is limited in extrapolation or generalizability and therefore the other RCT or the Real World Clinical Trial needs to be initiated. Of course, IITs can also be done pre-marketing, e.g., in a Phase 3b setting. While companies do conduct such Phase 4 studies, it is also good if investigators initiate their own research in the post-marketing environment.”

“It is time to do research in practice and contribute to clinical development and research,” Suvarna concludes. “It is time to inculcate that mindset of inquiry into observations in practice and have the hunger and thirst of trying to find answers. It is time to make time for truly investigator-initiated trials and not merely industry-initiated trials.”

1. Investigational New Drug Applications Prepared and Submitted by Sponsor Investigators: Guidance for Industry. Food and Drug Administration. May 2015 Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM446695.pdf.
2. Cobert B. FDA’s May 2015 draft guidance for investigator-initiated trials/studies. 3Ci Healthcare Connections. June 25, 2015. Available at http://www.c3ihc.com/blog/fdas-may-2015-draft-guidance-for-investigator-initiated-trials-studies/.
3. Suvarna V. Investigator-initiated trials. Perspect Clin Res 2012;3:119–121.


By Sue Coons, MA

This article was reprinted from Research Practitioner, Volume 17, Number 1, January-February 2016.

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