Proof of concept/safety studies

Other proof of concept/safety studies in dogs and rabbits... 

Fiorucci, S., Santucci, L., Gresele, P., Faccino, R.M., Del Soldato, P., and Morelh, A., Gastrointestinal safety ofNO-aspirin (NCX-4016) in healthy human volunteers a proof of concept endoscopic study. Gastroenterology, 124,600-607,2003. 

Phase I studies evaluate the pharmacokinetics and safety of the drug in a small number (tens) of healthy volunteers. Phase I studies are sometimes conducted in a small patient population (Proof of Concept studies) with a specific objective such as the validation of the relevance of preclinical models in man. The purpose of these studies may be the rapid elimination of potential failures from the pipeline, definition of biological markers for efficacy or toxicity, or demonstration of early evidence of efficacy. These studies have a potential go/no-go decision criteria such as safety, tolerability, bioavailability/PK, pharmacodynamics, and efficacy. Dosage forms used in Phase I or Proof of Concept studies must be developed with the objectives of the clinical study in mind. 

The filing of a full IND, with a formal coordinated writeup of all the supporting data, while necessary 40 years ago, is now an unnecessary requirement in the early-stage clinical programs of most large pharmas and CROs that do this work today. It is a barrier to the easy access to human studies that is needed for proof-of-concept studies (Phases 1 and 2a). There has been very little trouble in the past 20 years with early INDs filed by responsible individuals, corporations and institutions. The system can now be safety adjusted to recognise this fact, by scaling back the IND requirements for responsible entities, based on what has been learned in the past 40 years. 

Once the initial safety/tolerability of the investigational drug has been demonstrated in the initial Phase I trials, the compound is progressed into Phase II trials. These studies are performed in larger, quite often multi-center trials in the target patient population with the objective of providing so-called proof of concept information. The number of patients to be enrolled into these phase II trials is very much dependent on the therapeutic area and can range from 50-200 patients up to several hundreds. 

In a proof of concept study where BIBN 4096 BS was administered intravenously by a 10-min infusion to patients with migraine attacks as rated as moderate to severe, the investigators found response rates similar to the efficacy rates reported for triptans, together with good safety and tolerability profiles. The pharmacokinetics... 

These animal models of disease should be considered early on as potentially providing some of the data necessary for initiation of human studies. Besides utility as proof of concept, they can add to understanding dose response as well as help evaluate some safety endpoints. New products resulting from improved manufacturing can be compared with previously produced material using pharmacokinetic parameters. 

The preclinical assessment of blood products has been based on studies designed to answer specific questions on product-specific attributes with a consideration of the intended patient population. In many cases relevant animal models of the disease have been used to assess safety in addition to providing proof-of-concept information to support clinical development. 

Study designs should take into consideration the type of cells that will be evaluated, selection of a relevant animal model, including a model that mimics the intended clinical population or disease state, and the treatment regimen, including route of administration. In most cases animal models of disease will be the most relevant model to assess not only proof of concept but also safety. 

FDA is flexible in product testing for niAbs in early-stage feasibility cHnical trials intended to treat life-threatening conditions [5]. Feasibility clinical trials are pilot studies designed to provide an early characterization of safety and an initial proof of concept in specific patient populations. An immediately life-threatening condition is defined in 21 CFR 312.34 as a stage of disease in which there is a reasonable likelihood that death will occur in a matter of months or in which premature death is likely without early treatment. ... 

An appropriate level of exploratory subgroup analyses is warranted in any clinical trial. The objective of such analyses is typically hypothesis generating. Larger proportion of analyses tends to be exploratory in nature for an early phase study (e.g., a proof-of-concept study) in a relatively new therapeutic area where there is no approved drug in a similar class. However, even for later phase studies, such as a large phase 3 study or a long-term safety study. 

With such an in vivo proof of concept established, we profiled several of the CatA inhibitors in advanced models of cardiovascular diseases. These studies indicated a significant impact of CatA inhibition on several disease parameters including cardiac hypertrophy [2], Based on the outcome of these studies and its promising ADME and safety profile, one of our CatA inhibitors has now been progressed into phase I clinical trials. 

Phase Da Determine proof of concept Human safety Additional non-clinical safety studies to enable long-term dosing 25.7 months 10s kg... 

Several respondents indicated that animal models of disease have been used in proof of concept studies to determine efficacy, but that the use of these models can confound safety interpretation. However, other respondents were of the opinion that they can be a very effective way to get a quick evaluation of safety and efficacy. For example, the specificity of products may not be limited to species specificity, but also to physiological status, and appropriate safety or toxicokinetic data may not be revealed without the underlying disease pathology. 

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