Clinical holds

The FDA Accepts the Complete Response for Clinical Hold of FG-2216/FG-4592 for the Treatment of Anemia, April 2, 2008, http //www.astellas.com/en/corporate/news/ pdf/080402 eg.pdf (accessed July 6, 2010). 

At the end of 30 days, the FDA informs the Sponsor of its review finding. There may be additional information that the FDA requires the Sponsor to submit, in which case the trial is put on clinical hold until all queries are satisfactorily answered. If the FDA considers the information provided does not support the conduct of a trial or subjects may be at risk in a trial, the clinical hold is not lifted and the IND is not approved. 

Phase I, II, and III Trials An IND is submitted for each phase of clinical trial. Phases I to III. At any stage of the trial, the FDA has the authority to put clinical hold on the trial until deficiencies or safety issues are resolved. The Sponsor can request meetings with the FDA at various stages ... 

Clarifies the power of FDA to prevent or halt a clinical investigation of a new drug through use of a clinical hold. 

A great majority of botanical sponsors have taken advantage of the pre-IND consultation service provided by FDA. As a result, most IND applications were successful with initial submission and few (less than 20) were placed on clinical hold for safety concerns. However, despite the early success, many development programs and research projects have subsequently been suspended for various reasons. As of the above-mentioned cutoff date (April 30, 2004), nearly two-thirds (66%) of INDs still remain active (have not been placed on clinical hold, inactivated by FDA, or withdrawn by sponsor for lack of activities). To date, there have been no submissions of NDAs to FDA for marketing approval of botanical prescription drugs. 

If concerns are found, a deficiency letter will be sent, and if the deficiencies are serious enough to delay clinical trials the agency will impose a clinical hold on the product that can be lifted after the deficiencies are corrected. Clinical holds are classified as complete or partial, depending on whether the issues relate to the product or its manufacture or are specifically related to protocol concerns. Application sponsors should respond to clinical hold notifications promptly. Additionally, FDA is required to respond to completed responses within 30 days of receipt. Examples of reasons for clinical holds are... 

Communicate results of review of complete industry responses to FDA clinical holds No goal 90% within 30 days 90% within 30 days... 

Classifying Resubmissions in Response to Action Letters, May 14,1998. Center for Drug Evaluation and Research (CDER). Guidance for Industry. Submitting and Reviewing Complete Responses to Clinical Holds, May 14,1998. 

IND Process and Review Procedures (Including Clinical Holds) includes general IND review principles, policies, and procedures for issuing clinical holds of INDs, and processing and responding to sponsors complete responses to clinical holds. 

B) For purposes of subparagraph (A), a determination described in this subparagraph with respect to a clinical hold is that... 

C) Any written request to the Secretary from the sponsor of an investigation that a clinical hold be removed shall receive a decision, in writing and specifying the reasons therefor, within 30 days after receipt of such request. Any such request shall include sufficient information to support the removal of such clinical hold. 

Once an IND has been opened (submitted and approved), an annual report is required, as per 21 Code of Federal Regulations (CFR) 312.33. It is important to note that INDs are not formally approved by the FDA they go into effect 30 days after submission unless a clinical hold for cause is instituted. The IND Annual Report therefore provides reinforcing information indicating that a clinical hold is (still) not appropriate. 

At any time in the clinical trials process, the FDA is allowed to issue a clinical hold if it is deemed necessary. A clinical hold is an order to the sponsor to delay a proposed investigation or to suspend an ongoing investigation entirely. When a clinical hold is issued, no new subjects are allowed to enter the program, and patients already in the study must be taken off the drug unless discontinuing the treatment could interfere with patient safety. During the period from 1999 to 2001, the FDA... 

CJC-1295 Growth hormone Phasel (clinical hold) yeast with... 

Chen et al. (2008) reviewed the numbers and types of botanical IND applications received by the FDA from 1999 to 2007. A total of 225 botanical IND applications covering 12 therapeutic indications were received by the agency. The most common indication/target is oncology, followed by rheuma-tological analgesic and endocrine metabolic indications. Chen also noted that the proposed studies of 13% of the INDs submitted were placed on clinical hold due to unresolved safety concerns. 

An IND goes into effect 30 days after the FDA receives the IND, unless the FDA notifies the sponsor that the investigations described in the IND are subject to a clinical hold. It is possible, but not usual, that there may be earlier... 

The appropriate box(es) briefly describing the submission should be checked in item 11. It is possible that one IND amendment may contain protocol amendments and information amendments. In such a case, the applicable boxes are marked. If the filing is for the initial IND, a response to a clinical hold, an initial or follow-up IND safety report, a response to an FDA request for information, an annual report, or general correspondence, the appropriate box should be checked. Finally, there is a box if the sponsor is requesting reinstatement of an IND that has been withdrawn, inactivated, terminated, or discontinued. 

Details on the FDA s policy for the IND process and review procedures, including the handling of clinical holds, is presented in the FDA Manual of... 

The reduction in review time and increase in number of approvals have been the result of increased efforts and efficiency at the FDA and the preparation of better NDAs by pharmaceutical companies. Better communication between the FDA and applicants has also contributed to the improvement. In 1993, 26% of the 113 original NDAs were rejected by the FDA during the initial review for completeness. By 1997, the percentage of refuse-to-file actions had decreased to 1.6% for 124 original applications. These efficiencies have also spilled over into the IND arena, resulting in a lower percentage of clinical holds on a higher number of INDs received (16). 

When the FDA decides that a certcun clinical trial should be delayed, the agency contacts the sponsor within the 30-day period to initiate what is called a clinical hold —the delay of the clinical trial until potential problems or unanswered questions are addressed. Aside from the safety-related reasons mentioned above, the FDA may base a clinical hold on other grounds, including that the IND does not contain sufficient information to assess the risks of using the drug in clinical trials. 

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