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Human Clinical Trials,Marketing Authorization for Pharmaceuticals-ICH

From FDA/CBER, Sept 4, 2008, a follow up on an ICH Harmonised Tripartite Guideline document, 'Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals' (M3(R2) Current Step 2 version dated 15 July 2008). (1) For purposes of Supra readers, this document also provides the latest description of the conventional development of a pharmaceutical-- a stepwise process involving an evaluation of both the animal and human safety information. It is comprehensive yet very readable in this complex and technical area.
The Guidance states that it is generally recognized that the types of safety studies conducted in the evaluation of biotechnology-derived products are varied and should be determined in accordance with the ICH guideline for biotechnology-derived products. The present ICH guideline (M3) can provide general insight for biotechnology-derived products only with regard to timing of nonclinical studies relative to clinical development stage. Below are selected, abbreviated excerpts.
The purpose of this document is to recommend international standards for, and promote harmonisation of, the scope/duration of nonclinical safety studies recommended to support the conduct of human clinical trials of a given scope/duration and marketing authorization for pharmacueticals. It represents the consensus that exists among the regions of Europe, USA, and Japan. This guidance should facilitate the timely conduct of clinical trials, reduce the use of animals in accordance with the 3R (reduce/refine/replace) principles and reduce the use of other drug development resources. This should promote safe and ethical development and availability of new pharmaceuticals.

Guideline's Scope: The nonclinical safety study recommendations for the marketing approval of a pharmaceutical usually include safety pharmacology studies, repeated dose toxicity studies, toxicokinetic and nonclinical pharmacokinetic studies, reproduction toxicity studies, genotoxicity studies and, for drugs that have special cause for concern or are intended for a long duration of use, an assessment of carcinogenic potential. Other nonclinical studies including phototoxicity studies, immunotoxicity studies, juvenile animal toxicity studies, and abuse potential studies should be conducted on a case-by-case basis as appropriate. These types of studies and their relation to the conduct of human clinical trials are presented in this guideline.This guideline applies to the situations usually encountered during the conventional development of pharmaceuticals and should be viewed as providing general guidance for drug development.
Animal safety studies/human clinical trials should be planned/designed to represent an approach that is scientifically/ethically appropriate for the pharmaceutical under development.
Pharmaceuticals under development for indications in life threatening or serious diseases (e.g., advanced cancer, resistant HIV infection, and congenital enzyme deficiency disease) without current effective therapy might also warrant a case-by-case approach to both the toxicological evaluation and clinical development to optimise and expedite drug development. In these cases and for products using innovative therapeutic modalities (e.g., siRNA), as well as vaccine adjuvants, particular studies can/might be abbreviated, deferred, omitted, or added.

General Principles:...The goals of the nonclinical safety evaluation generally include a characterisation of toxic effects with respect to target organs, dose dependence, relationship to exposure, and when appropriate, potential reversibility. This information is helpful for the estimation of an initial safe starting dose and dose range for the human trials and the identification of parameters for clinical monitoring for potential adverse effects. The nonclinical safety studies, although limited at the beginning of clinical development, should be adequate to characterise potential toxic effects that might occur under the conditions of the supported clinical trial.
Human clinical trials are conducted to demonstrate the efficacy and safety of a pharmaceutical, starting with a relatively low exposure in a small number of subjects. This is followed by clinical trials in which exposure usually increases by duration and/or size of the exposed patient population. Clinical trials should be extended based on the demonstration of adequate safety in the previous clinical study(ies), as well as, additional nonclinical safety information that become available as clinical development proceeds.
Serious adverse clinical or nonclinical findings can influence the continuation of clinical trials and/or suggest the appropriateness of additional nonclinical studies. These nonclinical findings should be evaluated in light of the clinical results in determining the appropriateness of additional nonclinical studies and the nature of those studies.

Document History:
November 7, 1997- Approval by the Steering Committee under Step 2 and release for public consultation.(M3)
July 16, 1997-Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory.(M3)
November 9, 2000-Approval by the Steering Committee of minor revisions without further public consultation under Step 4 and recommendation for adoption to the three ICH regulatory bodies.M3(R1)
July 17, 2008-Approval by the Steering Committee of M3(R1) Revision under Step 2 and release for public consultation. M3(R2) Current Step 2 version: Approval by the Steering Committee of minor post Step 2 editorial correction.
At Step 2 of the ICH Process, a consensus draft text or guideline, agreed by the appropriate ICH Expert Working Group, is transmitted by the ICH Steering Committee to the regulatory authorities of the three ICH regions (the European Union, Japan and the USA) for internal and external consultation, according to national or regional procedures.

The Guidance itself is the best way to learn of the general and many specifics in pharmaceutical development. See below fold for additional, abbreviated yet long excerpts including:
Reproduction Toxicity Studies, [Men, Women Not Of Childbearing Potential (i.e., permanently sterilised, postmenopausal), Women of Childbearing Potential (WOCBP),
Pregnant Women]
Clinical Trials in Pediatric Populations,
Nonclinical Abuse Liability.
(1) http://www.fda.gov/cder/guidance/8500dft.htm

REPRODUCTION TOXICITY STUDIES: Reproduction toxicity studies should be conducted as is appropriate for the population that is to be exposed.
-Men can be included in Phase 1 and 2 trials prior to the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated dose toxicity studies .A male fertility study should be completed prior to the initiation of large scale or long duration clinical trials (e.g., Phase 3 trials).
-Women Not Of Childbearing Potential (i.e., permanently sterilised, postmenopausal) can be included in clinical trials without reproduction toxicity studies if the relevant repeated dose toxicity studies (which include an evaluation of the female reproductive organs) have been conducted. Postmenopausal is defined as 12 months with no menses without an alternative medical cause.
-Women of Childbearing Potential (WOCBP) For WOCBP there is a high level of concern for the unintentional exposure of an embryo or fetus before information is available concerning the potential benefits versus potential risks....It is imperative to minimize the risk to the embryo or fetus when including WOCBP in clinical trials. There are several approaches to achieve this objective. One approach is to conduct reproduction toxicity studies to understand the inherent risk of a drug and take appropriate precautions during potential exposures. A second approach is to limit the risk by taking precautions to prevent pregnancy during clinical trials. Precautions can include pregnancy testing, use of a highly effective method of birth control and study entry only after a confirmed menstrual period. Testing for pregnancy during the trial and subject education should be sufficient to ensure compliance with the measures designed to prevent pregnancy during the period of drug exposure (which could exceed the length of study). To support these approaches, informed consent should be based on any known pertinent information related to reproduction toxicity, such as a general assessment of potential toxicity of pharmaceuticals with related structures or pharmacological effects. If no relevant reproductive information is available, the potential for risks should be communicated. See also important variations/similarities among regions.
-Pregnant Women Prior to the inclusion of pregnant women in clinical trials, all the reproduction toxicity studies and the standard battery of genotoxicity tests should be conducted. In addition, safety data from previous human exposure should be evaluated.

CLINICAL TRIALS IN PEDIATRIC POPULATIONS: When pediatric patients are included in clinical trials, safety data from previous adult human exposure would usually represent the most relevant information and should generally be available before initiation of pediatric clinical trials. The appropriateness and extent of adult human data should be determined on a case-by-case basis. Extensive adult experience might not be appropriate prior to pediatric exposures (e.g., for pediatric-specific indications).

Results from repeated dose toxicity studies of appropriate duration in adult animals, the core safety pharmacology package, and the standard battery of genotoxicity tests should be available prior to the initiation of trials in pediatric populations. Reproduction toxicity studies relevant to the age and gender of the pediatric patient populations under study can also be important to provide information on direct toxic or developmental risks (e.g., fertility and peri-post natal developmental studies). Embryo-fetal developmental studies are not critical to support clinical studies for males or prepubescent females.

The appropriateness of juvenile animal toxicity studies should be considered only when previous animal data and human safety data are judged to be insufficient to support pediatric studies.
Generally, juvenile animal toxicity studies are not considered important for short term pharmacokinetic studies (e.g., 1 to 3 doses) in pediatric populations.
Depending on the indication of the drug, age of the pediatric population, and safety data from adult animal and human exposure, the appropriateness of juvenile animal study results prior to initiation of short duration multiple dose efficacy and safety trials should be considered.
The age of the study participants in relation to the duration of clinical study is among the most important considerations with respect to the timing of the juvenile animal toxicity study.
In all cases where an assessment of juvenile animal toxicity is recommended, the studies should be completed prior to initiation of long-term clinical trials in pediatric populations.
There can be cases where a pediatric population is the primary population; existing animal studies do not adequately address developmental concerns for target organs, and long term juvenile toxicity testing in a non-rodent would be valuable. In this case, a study initiated in the appropriate age and species of juvenile animals that covers the developmental period of concern can be appropriate. A non-rodent chronic study (e.g., 12 months duration in dog to cover the full development period in this species) combining the objectives of the standard chronic and separate juvenile animal toxicity study can be appropriate.

NONCLINICAL ABUSE LIABILITY: The evaluation of abuse liability should be considered for drugs that are distributed into the brain and produce central nervous system activity, regardless of therapeutic indication. Nonclinical studies should support the design of clinical evaluations of abuse potential, classification/scheduling by regulatory agencies, and drug labeling.

Nonclinical data collected early in the drug development process can be useful in identification of early indicators of abuse potential. These early indicators would typically be available prior to first human dose and include the PK/PD profile to identify duration of action, similarity of chemical structure to known drugs of abuse, receptor binding profile, and behavioural pharmacology/clinical signs from in vivo nonclinical studies. When no abuse potential is apparent from these early studies, extensive testing in nonclinical abuse liability models might not be warranted. If the active substance shows signals associated with known abuse liability patterns or when the active substance has a novel mechanism of action on the central nervous system, further nonclinical studies are recommended to support large clinical trials (e.g., Phase 3).
Three studies are often completed to evaluate the potential for abuse liability: drug discrimination, self-administration of the compound, and an assessment of dependence/withdrawal. ...A dose that produces a maximum plasma concentration several-fold the highest intended clinical exposure is considered appropriate for these nonclinical abuse studies. There are regional guidance documents on the conduct of nonclinical abuse liability assessment that can be helpful in designing specific abuse liability packages.

Supra readers may also be interested to learn more about the nature of earliest nonclinical studies used to support human clinical trials, for example:

SAFETY PHARMACOLOGY: The core battery of safety pharmacology studies includes the assessment of effects on cardiovascular, central nervous and respiratory systems, and should generally be conducted prior to human exposure. If warranted, supplemental and follow-up safety pharmacology studies can be conducted during later clinical development.
TOXICOKINETIC AND PHARMACOKINETIC STUDIES: In vitro metabolic data for animals and humans, and exposure data in animals should be evaluated prior to initiating human clinical trials. Further information on absorption, distribution, metabolism and excretion in animals should be available prior to exposing large numbers of human subjects or treating for long duration (generally prior to Phase 3).
ACUTE TOXICITY STUDIES: Historically, acute toxicity information has been obtained from single dose toxicity studies in two mammalian species using both the clinical and a parenteral route of administration. However, such information can be obtained from appropriately conducted dose escalation studies or short duration dose ranging studies that define a maximum tolerated dose in the general toxicity test species. ...
In some specific situations (e.g., microdose studies) acute toxicity or single dose studies can be the primary support for single dose studies in humans. In these situations, because these nonclinical studies are conducted to support human safety, the high dose selection can be different than that described above, but should be adequate to support the intended clinical dose and route. These studies should be performed in compliance with GLP and lethality should not be an intended endpoint.
Information on the acute toxicity of pharmaceutical agents could be useful to predict the consequences of human overdose situations and should be available prior to Phase 3. An earlier assessment of acute toxicity could also be important for therapeutic indications for which patient populations are at higher risk for overdosing (e.g., depression, pain, and dementia) in out-patient clinical trials.
REPEATED DOSE TOXICITY STUDIES: The recommended duration of the repeated dose toxicity studies is usually related to the duration, therapeutic indication and scope of the proposed clinical trial. In principle, the duration of the animal toxicity studies conducted in two mammalian species (one non-rodent) should be equal to or exceed the duration of the human clinical trials up to the maximum recommended duration of the repeated dose toxicity studies. See 'Clinical Development Trials Marketing Authorization' and 'Marketing Authorization'
ESTIMATION OF THE FIRST DOSE IN HUMAN: The estimation of the first dose in humans is an important element to safeguard the safety of subjects participating in first-in-human studies.
It is recognized that in some cases insight on human physiology/pharmacology, knowledge of drug candidate characteristics and therapeutic target relevance to disease are benefited by earlier access to human data. Streamlined early exploratory approaches can accomplish this end. Exploratory clinical studies for the purpose of this guidance are those intended to be conducted early in Phase 1, involve limited human exposure, have no therapeutic or diagnostic intent, and are not intended to examine maximum tolerated dose. They can be used to investigate a variety of parameters such as pharmacokinetics, pharmacodynamics and other biomarkers.
The amount of nonclinical supporting data that is appropriate in these situations will be dependent on the extent of proposed human exposure, both with respect to the maximum clinical dose used and the duration of dosing. Five different exploratory clinical approaches are described, together with the nonclinical testing programs that would be recommended in these particular approaches. However, other approaches not described in this guidance should be discussed and agreed upon with the appropriate regulatory authority. The use of these approaches is expected to reduce overall animal use in drug development.
See:Microdose Studies, Single Dose Studies up to Sub-therapeutic or Intended Therapeutic Range, Multiple Dose Studies.
Appropriate starting doses and stopping doses for each approach are included in Table 3.

GENOTOXICITY STUDIES: The genotoxicity studies recommended supporting Exploratory Clinical Study approaches are discussed in Section 7.

CARCINOGENICITY STUDIES:If carcinogenicity studies are recommended for the clinical indication, they should be conducted for a/the marketing application. Only in circumstances where there is a significant cause for concern for carcinogenic risk should the study results be submitted to support clinical trials.
OTHER TOXICITY STUDIES:Additional nonclinical studies (e.g., to identify potential biomarkers, to provide mechanistic understanding) can be useful if previous nonclinical or clinical findings with the product or related products have indicated special safety concerns.


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