What are the benefit-risk considerations during the development of your drug and how to avoid clinical hold?
On September 27-28, the FDA SBIA REdI Fall Conference took place in Rockville, MD. HW was there and reports highlights of the drug track of the meeting.
FDA reviewers and administrators explained the process to prepare an Investigational New Drug (IND) Application and methods to communicate with FDA. They highlighted the importance of reaching out to FDA early on during the drug development.
Charu Mullick, MD, Medical Officer at the Center for Drug Evaluation and Research (CDER), division of antiviral products, presented the benefit-risk considerations in drug development. She emphasized that the regulatory decision relies on the benefits, risks and disease that the drug is intended to treat. Furthermore, using a consistent and systematic approach when considering the benefit-risk assessment is critical. The outcomes of regulatory decisions are affected by many considerations including: benefit of the drug, safety (e.g. human safety data, toxicology, other nonclinical data, class-related toxicity concern), nature and severity of the target condition, the medical need, the availability of alternative therapy, areas of data gap, specific information regarding the drug or intended indication. Case studies for the division of antiviral products were provided.
One case study involved safety concerns (i.e. drug-induced liver injury) during a phase 2 clinical trial of an ongoing Human Immunodeficiency Virus (HIV) clinical program. As the decision took in consideration the trial patients populations (naïve HIV-infected patients with other alternative treatment available and experienced HIV infected patients with limited options) the decision was to place the trial in partial hold to allow dosing in treatment-experienced HIV infected patients. In a second case study, toxicity was identified in a 39-week chronic toxicology study while the clinical program was ongoing. This case study related to a treatment of genital herpes in immunocompetent adults using a novel mechanism of action. The initial toxicology data submitted with the initial IND did not raise any concern but during the phase 2 clinical trial, severe drug-related toxicities in the chronic toxicology study resulted in unscheduled animal sacrifice. When toxicity is identified in animals, it is important to evaluate whether the toxicity was identified in one or more than one species and whether the target organ was involved together with the extent of the severity. In this case, it was determined that human subjects would be exposed to unreasonable and significant risk of illness or injury and the IND was placed on full clinical hold.
What are the options after a full clinical hold? The review division will communicate to the sponsor the reasons for the clinical hold and will provide information that would be required to resolve the hold issues. With serious toxicities, the options to resolve the hold issue are limited.
The sponsor could address the nonclinical toxicity findings by – demonstrating that the toxicity is specific to an animal species and not relevant to humans, – demonstrating a study specific issue explaining the toxicity, – identifying a patient population for which the benefit-risk assessment would be favorable. The latter is likely to be the most feasible approach. In this case scenario, the program is revised to target patients who are immunocompromised with resistant virus. Indeed, an investigational drug of new class and mechanism of action may help avoid common resistance pathways. But due to limited treatment options in this population, it will be important to carefully find the acceptable dose and the limit to the dose/duration based on data obtained in clinical trials to date. A boxed warning will be added to the labeling due to the considerable toxicity.
The take-home message was to remember that the context matters and the totality of data provided is taken into consideration when assessing the benefit-risk of a drug.
Maria Cecilia Tami, PhD, from the FDA CDER, Office of pharmaceutical quality (OPQ) and Office of Biotechnology Products (OBP) presented case studies for biologics regulated in CDER. Those include proteins greater than 40 amino acids and derived from living material. Dr Tami, provided an overview of how FDA reviewers review an IND application based on a drug’s safety and effectiveness. Also presented, were the requirements for testing of the cell bank, including revealing the identity of expected species, the purity with the potential type of contaminants and the testing for adventitious viruses. One of the case study presented was about a recombinant protein produced in CHO. In that case, the cumulative log10 reduction factor (LRF) did not meet the safety requirements to avoid potential patient exposure to viral particles. Furthermore, insufficient information was provided to demonstrate the appropriateness of the model used. Altogether, the data provided lead to a clinical hold as the sponsor was unable to determine robust viral clearance of the downstream manufacturing process and acceptable safety margin.
What were the sponsor’s options after the clinical hold? The sponsor repeated the viral clearance studies and also added an additional viral clearance step, demonstrated higher cumulative log10 reduction value (LRV), reached acceptable viral safety margin and finally demonstrated that the process parameters in the scale-down model was representative or at least compared to the at-scale process. Altogether, the additional data allowed the removal of the clinical hold.
Dr Tami also highlighted the importance to submit to FDA both tabular and primary data for the drug substance characterization. The release/characterization tests should cover safety, purity, impurities and characterization, identity, potency and protein content. It is important to note that early in the drug development the release specifications are broader and methods together with strategies should be discussed with FDA.
In a second case study for a recombinant protein, stability data for only the toxicology lot and not the proposed clinical lot was submitted in an original IND submission. The toxicology lots showed a time-dependent increase in impurities by Reverse-Phase HPLC through 6 months of storage under recommended storage conditions of -70°C leading to a clinical hold. This decision was made as there was no assurance that the proposed clinical lot would remain stable throughout the planned duration of clinical study. Once the sponsor was able to provide sufficient real-time stability data, including the primary data for the clinical lot to ensure stability during the clinical study, the clinical hold was removed.
A sponsor should keep in mind that the CMC information to support a phase 1 IND should be focused on the safety of the investigational product.
Overall, a good planning of the drug development and mitigating the risks will help the sponsor to avoid a clinical hold and if a clinical hold is issued, there are ways to overcome it. HW can assist you throughout your drug development including assisting you in planning of your regulatory strategy but also providing advice on the suitability of the method used and mitigating the risks t
Nitisha Pyndiah, PhD, is a Consultant where she provides advice for the development of biological, biotechnological, and biosimilar products.
Nitisha provides expertise in the areas of virology, molecular biology, microbiology, immunology, immunogenicity, quality control, GLP and GMP. She prepares and evaluates CMC sections, including FDA meeting documents; and conducts scientific and regulatory gap analyses. She supports technical, strategic, and operational regulatory affairs for recombinant proteins, monoclonal antibodies, and vaccines.