Evaluation of Preclinical Data to get to First in Man

By: GABRIEL FIOSSI ASSAGBAMATRIKEL NR: 9027395

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OUTLINE Introduction Notable Disasters in First In Human Trials Guidance for Industry and General Principles regarding FIH trials General guidelines with respect to EMA General guidelines with respect to FDA Conclusion References

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IntroductionIn the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered.

Historically, drugs were discovered through identifying the active ingredient from traditional remedies or by serendipitous discovery.

Example being Alexander Fleming´s discovery of Penicillin in 1928.

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Notable Disasters in First in Human TrialsThe TGN1412 DISASTER (2006)

CD28 superagonist antibodies can cause activation and proliferation of regulatory T cells regardless of signal received by T-cell receptor. Monoclonal anti-CD28 antibody such as TGN1412 was capable of activating T cells by binding to CD28 receptor irrespective of T-cell receptor activation and hence it was termed as a CD28 superagonist. 

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Notable Disasters in First in Human Trials

TGN1412 was administered to six healthy human volunteers in phase 1 clinical trial conducted by Paraxel for TeGenero at Northwick hospital in London, UK, minutes after the first infusion of humanized CD28 superagonist TGN1412, all patients started suffering from severe adverse reaction resulting from rapid release of cytokines by activated T cells.

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TGN1412 DISASTER CONTINUATIONTGN1412 study problem Detail Learning PointInterpretation of preclinical (primate) studies

Low-level cytokine release in primate studies should have promoted more caution

Minor but potentially important effects in preclinical studies should raise caution in crossing the species barrier

Use of human in vitro studies Insufficient in-vitro human studies were performed

In vitro studies on human material as close as possible to the target tissue can be important.

Choice of starting dose Subtle difference between primate and human target ligand may explain marked difference in potency – the calculation of an initial dose based on a fraction of predicted ‘no adverse effect level’ proved dangerously wrong

Prediction of risk and dose range from animal studies may prove unreliable: extra caution with wider margins of safety are required with ‘potentially risky modes of action’

Dosing interval between subjects No ‘proper interval’ allowing for the observation of possible side effects was left between the dosing of one subject and the next

In fisrt-in-man studies, investigators should expect the unexpected

Preparation for adverse events Preparation for possible adverse events (cytokine storm) was inadequate – investigators did not expect it, recognize it or treat early.

Where there is a known theoretical risk, investigators should plan for its potential occurrence

Summary of learning points from the TGN1412 phase I study

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FIALURIDINE DISASTERFialuridine, a thymidine analog having antiviral activity against Hepatitis B virus showed adverse reactions in phase 2 clinical trials leading to death of five human volunteers due to severe hepatic toxicity and lactic acidosis

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Call for strict regulations regarding FIH trials

The above-mentioned incidents especially the TeGenero incident was an alarming call for the researchers and also for the trial approving regulatory authorities on toxicity-related unpredictability of new drugs in human subjects especially for biological with a novel mechanism of action like TGN1412.

The recommendations fall into several broad categories: preclinical development that is both directed and consultative; evidence based transition to testing in humans; more open regulatory and ethical review, including independent scientific expertise; and most importantly, the need for more transparency

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Guidance for Industry in Clinical Trials Objectives of the GuidanceThis guidance should facilitate the timely conduct of clinical trials andreduce the unnecessary use of animals and other resources. This shouldpromote safe and ethical development and availability of newpharmaceuticals.

BackgroundThe present guidance represents the consensus that exists among the ICH regions regarding the scope and duration of nonclinical safety studies to support the conduct of human clinical trials for pharmaceuticals.

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General PrinciplesThe goals of the nonclinical safety evaluation include: A characterization of toxic effects with respect to target organs, dose dependence, relationship to exposure, and potential reversibility

SAFETY PHARMACOLOGYIncludes the assessment of effects on vital functions, such as cardiovascular, central nervous, and respiratory systems

TOXICOKINETIC AND PHARMACOKINETIC STUDIESExposure data in animals should be evaluated prior to human clinical trials. Further information on ADME in animals should be made available to compare human and animal metabolic pathways.

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General Principles SINGLE DOSE TOXICITY STUDIESEvaluated in two mammalian species prior to the first human exposure

REPEATED DOSE TOXICITY STUDIESRelated to the duration, therapeutic indication, and scale of the proposed clinical trial.

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Birth of EMA Guidelines Committee for Medicinal Products for Human Use (CHMP) of the European

Medicines Agency (EMEA) was working on creating a guideline on strategies to identify and mitigate risks for FIH clinical trials with investigational medicinal products. (March 2006)

‘‘Requirements for First-in-Man Clinical Trials for Potential High-Risk Medicinal Products’’ (January 2007)

Draft completed Six months later, with comments and consultations from Institutes and Industries taken and Considered

‘‘Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products’’

The guideline was adopted by the CHMP on July 19, 2007, and came into effect on September 1, 2007

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General guidelines with respect to EMA

Guiding Objective: intended to assist sponsors in the transition from nonclinical to early clinical development

The guideline is not a stand-alone document and should be read in conjunction with several nonclinical and clinical EU guidelines.

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These include: Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for

Pharmaceuticals (ICH M3), CPMP/ICH/286/95 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (ICH S6),

CPMP/ICH/302/95 The Non-Clinical Evaluation of the Potential for Delayed Ventricular Repolarisation

(QT Interval Prolongation) by Human Pharmaceuticals (ICH S7B), CPMP/ICH/423/02 Safety Pharmacology Studies for Human Pharmaceuticals (ICH S7A),

CPMP/ICH/539/00 Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies (ICH

S3A), CPMP/ICH/384/95 Position Paper on the Non-Clinical Safety Studies to Support Clinical Trials with a

Single Micro Dose, CPMP/SWP/2599/02 Guideline for Good Clinical Practice (ICH E6), CPMP/ICH/135/95 General Considerations for Clinical Trials (ICH E8), CPMP/ICH/291/95 EUDRALEX Vol. 10—Clinical Trials (in particular, chap. 1: Application and

Application Form, and chap. 2: Monitoring and Pharmacovigilance)

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Processes in Evaluation of Data

Maximum Duration of Clinical Trial Recommended Minimum Duration of Repeated-Dose Toxicity Studies to Support Clinical Trials

  Rodents Non-rodents

Up to 2 weeks 2 weeksa 2 weeksa

Between 2 weeks and 6 months Same as clinical trialb Same as clinical trialb

> 6 months 6 monthsb, c 9 months b, c, d

Recommended Duration of Repeated-Dose Toxicity Studies to Support the Conduct of Clinical Trials:

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Categories Evaluated in First In Human Trials Local tolerance studies

Genotoxicity studies

Carcinogenicity studies

Reproduction toxicity studies Clinical trials in paediatric

populations Immunotoxicity

Photosafety testing

Nonclinical abuse liability

Other toxicity studies

Combination drug toxicity testing

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General guidelines with respect to FDAInvestigational New Drugs Application and Evaluation is handled

by the Center for Drug Evaluation and Research (CDER)

Guiding Objective: Assure that safe and effective drugs are available to the American peopleAchieved through:

Whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh its risks.

Whether the drug's proposed labeling is appropriate, and, if not, what the drug's labelling should contain.

Whether the methods used in manufacturing the drug and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity.

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Processes in Evaluation of DataData and Information required by the CDER

includes generally: Animal Pharmacology and

Toxicology Studies

Manufacturing Information

Clinical Protocols and Investigator Information

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Certain outcomes after Review Clinical Hold CDER uses this when it does not believe, or cannot confirm, that the study can be conducted without unreasonable risk to the subjects/patients.When a clinical hold is issued, a sponsor must address the issue that is the basis of the hold before the order is removed.

Notify SponsorNotified immediately by telephone by the division director followed by a letter within five working days following the telephone call and a response expected and decisions taken within 30 days.

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Sponsor Notified of Deficienciesthe division informs the sponsor that it may proceed with the planned clinical trials, but that additional information is necessary to complete or correct the IND file, or that there are issues that need to be addressed prior to a marketing application (NDA) submission.

Study OngoingAfter CDER's 30-day initial review period expires, clinical studies can be initiated. Subsequent clinical trials may begin immediately upon submission of the clinical protocol to the IND

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CONCLUSIONWith the advent of new diseases and infections, there is the need for increased research in getting solutions to fight these new emerging diseases

But the problem is how to move the drug from the lab bench to the suffering masses

And in any clinical research, SAFETY of the patient is the cardinal point

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Preclinical Research can fall short in 3 ways1. Failure to predict human risks

2. Clinical benefits that fail to materialise in humans

3. Prediction of non-existent risks in humans

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Much could be done to make FIH trials a more ethical activity. We should not lose sight of an

uncomfortable reality: FIH trials expose healthy people with limited economic opportunities and ill people with limited health options to harm for

the benefit of others.

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Investigators and regulators must not allow the policy enthusiasm for translational science to

overshadow the commitment to protect human subjects.

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