Sponsors spend countless hours developing Investigational New Drug (IND) applications, which are the US FDA’s regulatory gateways for conducting clinical trials of investigational drug and drug-device combination products. The stakes are high for companies as they submit their initial IND, as the ability to start clinical trials hinges on the activation of the IND. But an IND filing is not trivial.
Some IND filings do not go as planned. If safety concerns arise from the review of the IND, the FDA can place sponsors on partial or full clinical holds. Often, such a development is a disaster for companies striving to move forward to conduct their clinical development programs.
A clinical hold can signal to investors and others that the investigational product may have safety issues, where management may have chosen an ill-advised initial regulatory strategy, that the firm may lack some technical expertise, or that the management team isn’t prepared for the challenges of drug development. It is essential to get the IND filing right.
The Center for Drug Evaluation and Research (CDER) reported that from 2012 to 2013, of 1,410 IND applications received, 125 (9%) were placed on clinical holds and half of those applications were removed from clinical hold within one year.
Types of and Reasons for Clinical Holds
Clinical holds are orders from the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. During the 30-day review period of the initial IND application, the FDA reviews submitted data to ensure that clinical study participants will not be exposed to unreasonable risks in clinical testing and that the proposed study design is appropriate based on the study objectives. A complete clinical hold suspends all clinical work under the IND, whereas a partial clinical hold suspends only part of the clinical work proposed or being conducted under the IND (for example, one treatment arm of a study, or one entire study but not another proposed ongoing trial).
Clinical holds may be issued for Phase 1, 2, and/or 3 studies due to the following reasons:
- human subjects being subjected to unreasonable and significant risk of illness or injury
- the clinical investigator is not scientifically trained or experienced to conduct the study
- the investigational brochure is misleading, erroneous, or incomplete
- the information presented in the IND application does not sufficiently address the risk to the participants of the study
- the protocol is deficient on design to meet its stated objectives
A clinical hold can be issued for ongoing trials due to safety concerns that arise during the study. For example, if an ongoing study reports significant unexpected adverse reactions, the FDA can ask for an amendment to the protocol to minimize potential risks to current or new patients. If the hazard is considered significant, FDA can impose a clinical hold to suspend enrollment of new patients, require all study participants immediately stop taking the investigational product, halt a particular treatment arm or dose group, or some variation to limit the identified risks. Of course, such mid-study suspensions can render the utility of data collected in the study problematic from a statistical standpoint, as such holds represent a major departure from prospectively defined methods.
Premier Consulting Expertise in Clinical Holds
Moving to get an IND off of a clinical hold can be challenging, as the issues are often complex and reflect qualitative arguments about benefit-risk, nuances in clinical study design, the practical operational effects of trial changes, and more. Commonly, sponsors placed on clinical hold also damage their credibility with the FDA if the proposed trial design was inadequate in some meaningful way. Time is always of the essence, sponsors need to (re)initiate their studies, and they need to reestablish credibility with the Agency.
Premier Consulting has helped a number of sponsors facing clinical holds issued by the FDA. For example, when a sponsor was issued a partial hold for not providing sufficient information to assess human risks to human subjects, the sponsor engaged Premier Consulting for help. Premier Consulting requested a clarification of the clinical hold immediately after receiving the hold. The company then submitted a complete response letter addressing the FDA’s concern. This resulted in the FDA removing the clinical hold, and allowing the sponsor to proceed to clinical studies using the investigational drug.
Type A Meetings
Premier Consulting also has experience with helping sponsors on full clinical holds, including success scheduling high-priority Type A meetings (priority meetings that can occur within 30 days) with the FDA.
For example, a sponsor came to Premier Consulting on clinical hold for providing insufficient information to the FDA for reviewers to adequately assess risks to human subjects. The investigator brochure was considered by the FDA to be misleading, erroneous, or materially incomplete. The sponsor had also submitted information on clinical investigators the FDA considered unqualified to conduct the proposed clinical trial.
Premier Consulting identified the major issues with the IND application as a lack of safety information, chemistry manufacturing and controls (CMC) deficiencies, and an incorrectly formatted investigator’s brochure. Premier Consulting was able to determine exactly what information the FDA required from the sponsor and designed a clinical protocol that could address the FDA’s concerns. The FDA agreed with the response and the clinical hold was removed.
Clinical Study Protocols
Premier Consulting has long recognized the value of carefully crafting clinical study protocols to anticipate and address the FDA’s potential concerns, and has deep expertise in developing study plans that the FDA considers appropriate. Premier Consulting also engages with the FDA in pre-IND meetings to proactively address any potential questions or concerns. This step helps ensure a successful IND submission, as; the reviewers will have become acquainted with the product and proposed study plan; Premier Consulting will have posed and received feedback on key questions; the Agency will have signaled any concerns; and study design discussions took place in person. Such a proactive approach is prudent and a recipe for success.
Premier Consulting’s goal for sponsors submitting IND applications is to reduce the risk of a potential clinical hold. Submitting a pre-IND Advice Request to the FDA and receiving early feedback on proposed trials and other factors can alleviate the financial and public relations implications for sponsors and investors that can result from clinical holds.
To learn more about ways Premier Consulting can help avoid or navigate a clinical hold, contact us.
Jason E Moore, MS, MBA, RAC
Vice President, Global Program Management