rymat drug development training module

The Drug Development Process

RyMat IncSolution Provider to the Pharmaceutical Industry


The Drug Development Process – Clinical Development

The Progressive Stages of Clinical Development

• Following the “Drug Discovery” process, a “Drug Candidate” is nominated for clinical development

• A single “Lead Compound” is chosen to move forward.

• There may also be additional “back-up” compounds nominated, but treated with a (much) lower priority.



Stages of Clinical Development

1.) Preclinical

2.) Phase I

3.) Phase II (Phase IIa & Phase IIb)

4.) Phase III

5.)Registration

6.) Commercial Launch

7.) Phase IV


The Drug Development Process – Preclinical Development

Preclinical Development

• Before testing a new medicine in humans, researchers conduct extensive “preclinical testing” of the molecule.

• They perform various experiments with “in vitro” (i.e. in a petri dish, vial, or beaker in the laboratory) or in animal models (usually simplerspecies such as rodents).

• The activity of the drug candidate is carefully examined under many different conditions prior to moving it into human testing in medical clinics.


Preclinical Development (continued)• Under FDA requirements, a company must first submit data showing that the drug is reasonably safe for use in initial, small-scale clinical studies. • Genotoxicity screening is performed, as well as investigations on drug absorption and metabolism, the toxicity of the drug's metabolites, and the speed with which the drug and its metabolites are excreted from the body.



Preclinical Development (continued)

At the preclinical stage, the FDA will generally ask, at a minimum, that the developers:

(1) develop a pharmacological profile of the drug;

(2) determine the acute toxicity of the drug in at least two species of animals.

(3) conduct short-term toxicity studies ranging from 2 weeks to 3 months, depending on the proposed duration of use of the substance in the proposed clinical studies.



Preclinical Development (continued)

Sponsor/FDA Meetings (Pre-IND) • Prior to clinical studies, the sponsor needs evidence that the compound is biologically active, and both the sponsor and the FDA need data showing that the drug is reasonably safe for initial administration to humans.



Investigational New Drug Application • The investigational new drug (IND) application is the result of a successful preclinical development program.

• The IND is also the vehicle through which a company advances to the next stage of drug development known as clinical trials (human trials).

• The IND is not an application for marketing approval. • It is a request for an exemption from the Federal statute that prohibits an unapproved drug from being shipped in interstate commerce.



Investigational New Drug Application (continued) • Animal Pharmacology and Toxicology Studies Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.

• Manufacturing Information Information pertaining to the composition, manufacture, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed as to ensure the company can adequately produce and supply consistent batches of the drug.



Investigational New Drug Application (continued)

• Clinical Protocols and Investigator Information

Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators—professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties.



Phase 1 Considerations•CMC safety issues as they relate to the quality aspects of product

•What is the risk for human subjects? Are there any signals from preclinical studies?

•The product class and the individual product affect, to some extent, the type and extent of information needed to assess safety.

–Often novel and complex products require additional information to address unknowns and added complexity (e.g., transgenic, xenotransplantation)



The Drug Development Process – Phase I Clinical Development

Phase I Clinical Development• Phase I clinical trials are designed to examine the safety of a drug candidate.

• Further clinical trials and development cannot happen unless Phase I trials demonstrate the drug candidate to be reasonably safe when administered to humans.• Some side effects may be acceptable in relation to the severity of the targeted disease (i.e. chemotherapy).• Participants in Phase I are closely monitored for the smallest indication of harm caused by the medicine.


Phase I Clinical Development (continued)• Safety is the key issue. Thus these trials are purposely conducted with a small scope (limited number of participants).

• An attempt is made to establish the dose range tolerated by volunteers for single and for multiple doses. .

•Phase I trials are sometimes conducted with severely ill patients (e.g. in the field of cancer).



Phase I Clinical Development (continued)

• In Phase 1 studies, CDER can impose a clinical hold (i.e., prohibit the study from proceeding or stop a trial that has started) for reasons of safety, or because of a sponsor's failure to accurately disclose the risk of study to investigators.

FDA Role in Phase I

CDER = Center for Drug Evaluation & Research



Phase I Clinical Development

Phase I Clinical Development is important

Why?

Because that is when the dosage form is beginning tobe determined.



Phase IIa Clinical Development

•Pilot clinical trials (“Pilot” means focused on obtaining information and working out trial logistics) evaluate efficacy (and safety) in selected populations of patients with the disease or condition to be treated, diagnosed, or prevented.

•Objectives may focus on dose-response, type of patient, frequency of dosing, or numerous other characteristics of safety and efficacy.



Phase IIb Clinical Development

Well-controlled trials to evaluate efficacy (and safety) in patients with the disease or condition to be treated, diagnosed, or prevented.

These clinical trials usually represent the most rigorous demonstration of a medicine’s efficacy. Sometimes referred to as pivotal trials.



Phase II Clinical Development

• Phase II clinical trials are designed to further assess safety and evaluate efficacy in humans over the short term.

• Phase II clinical trials help set up parameters (e.g. dosage) of the longer-term Phase III trials.

• Phase II trials are typically placebo controlled and double blinded.

• Neither the patient nor the medical personnel know whether the patient is receiving the drug or the placebo.



Phase II Clinical Development (continued)

• These trials are larger in scope than Phase I and take more time.• In an effort to save time and money, some companies try to minimize the size and scope of Phase II trials.

• Some companies rely on information from preclinical and Phase I trials to design comprehensive Phase II trials that can clearly demonstrate the efficacy (or lack thereof) of a drug before a Phase III trial.

• This approach minimizes the risk of unpleasant surprises following the far more expensive Phase III trials.



Phase III Clinical Development•Phase III trials are designed to prove the efficacy and confirm the safety of the drug.

• They are usually double-blinded and placebo-controlled and can involve hundreds or even thousands of patients over many months or even years.

• Though the numbers of patients involved can be great, the risks are relatively minimal because of the earlier testing to establish safety.



Phase IIIa Clinical Development

•Trials conducted after efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug Application (NDA) or other dossier. •These clinical trials are conducted in patient populations for which the medicine is eventually intended.

•Phase IIIa clinical trials generate additional data on both safety and efficacy in relatively large numbers of patients in both controlled and uncontrolled trials.



Phase IIIa Clinical Development

•Clinical trials are also conducted in special groups of patients (e.g. renal failure patients), or under special conditions dictated by the nature of the medicine and disease.

•These trials often provide much of the information needed for the package insert and labeling of the medicine.



Phase IIIb Clinical Development•Clinical trials conducted after regulatory submission of an NDA or other dossier, but prior to the medicine’s approval and launch. •These trials may supplement earlier trials, complete earlier trials, or may be directed toward new types of trials (e.g. quality of life, marketing) or Phase IV evaluations. •This is the period between submission and approval of a regulatory dossier for marketing authorization. •Comparisons to standard therapy (termed comparator studies) can be included in either Phase IIIa or Phase IIIb.



Phase II & III Clinical Development

FDA Involvement• In both Phase 2 and 3, CDER can impose a clinical hold if a study is unsafe (as in Phase 1), or if the protocol is clearly deficient in design in meeting its stated objectives.



Phase IV/Registration• Once all phases of clinical testing have been completed, if the data warrants it, the company applies to the Food and Drug Administration for regulatory approval to market the medicine in the United States. • If the FDA agrees that the data proves the safety and efficacy of the drug, approval may come in several months or years, with those medicines with the most urgent medical need typically approved more quickly.

• The company should work closely with regulatory agencies at all stages of clinical development to help ensure it can provide needed data to obtain approval as quickly as possible.



New Drug Application • Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. • The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) become part of the NDA.

• The components of any NDA are, in part, a function of the nature of the subject drug and the information available to the applicant at the time of submission. • The NDA must provide all relevant data and information that has been collected during the product's research and development.



New Drug Application (continued)

• Although the quantity of information and data submitted in NDAs can vary significantly, the components of NDAs are more uniform.

• NDAs can consist of as many as 15 different sections:



New Drug Application (continued)•Index; •Summary; •Chemistry, Manufacturing, and Control; •Samples, Methods Validation Package, and Labeling; •Nonclinical Pharmacology and Toxicology; •Human Pharmacokinetics and Bioavailability; •Microbiology (for anti-microbial drugs only); •Clinical Data; •Safety Update Report (typically submitted 120 days after the NDA's submission); •Statistical; •Case Report Tabulations; •Case Report Forms; •Patent Information; •Patent Certification; and •Other Information.


NDA Actions • Once an approval, approvable, or non-approvable recommendation is reached by the reviewers and their supervisors, the decision must be evaluated and agreed to by the director of the applicable drug review division or office.

• The division director generally serves as the final FDA ruling. • Once the division director (or office director, as appropriate) signs an approval action letter, the product can be legally marketed starting that day in the United States.



Phase IV•Studies or trials conducted after a medicine is marketed to provide additional details about the medicine’s efficacy or safety profile.

•Different formulations, dosages, durations of treatment, medicine interactions, and other medicine comparisons (termed comparator studies) may be evaluated.

•New age groups, races, and other types of patients can be studied.

•Detection and definition of previously unknown or inadequately quantified adverse reactions and related risk factors are an important aspect of many Phase IV studies.



Phase IV•If a marketed medicine is to be evaluated for another (i.e. new) indication, then those clinical trials are considered Phase II clinical studies.

•The term post-marketing surveillance is frequently used to describe those clinical studies in Phase IV (i.e. the period following marketing) that are primarily observational or non-experimental in nature, to distinguish them from well controlled Phase IV clinical trials or marketing studies.


Other Types of Approvals/Reviews


Accelerated Development/Review Other Types of Approvals/Reviews

• Accelerated development/review is a highly specialized mechanism for speeding the development of drugs that promise significant benefit over existing therapy for serious or life-threatening illnesses for which no therapy exists. • This process incorporates several novel elements aimed at making sure that rapid development and review is balanced by safeguards to protect both the patients and the integrity of the regulatory process.

• The fundamental element of this process is that the manufacturers must continue testing after approval to demonstrate that the drug indeed provides therapeutic benefit to the patient. If not, the FDA can withdraw the product from the market more easily than usual.



Treatment IND • Treatment Investigational New Drugs are used to make promising new drugs available to desperately ill patients as early in the drug development process as possible. • FDA will permit an investigational drug to be used under a treatment IND if there is preliminary evidence of drug efficacy and the drug is intended to treat a serious or life-threatening disease, or if there is no comparable alternative drug or therapy available to treat that stage of the disease in the intended patient population.

• In addition, these patients are not eligible to be in the definitive clinical trials, which must be well underway, if not almost finished.



Treatment IND (continued)

• An immediately life-threatening disease means a stage of a disease in which there is a reasonable likelihood that death will occur within a matter of months or in which premature death is likely without early treatment. • Treatment INDs are made available to patients before general marketing begins, typically during Phase 3 studies.

• Treatment INDs also allow FDA to obtain additional data on the drug's safety and effectiveness.



Parallel Track

• The "parallel track" policy was developed by the U.S. Public Health Service in response to AIDS.

• Under this policy, patients with AIDS whose condition prevents them from participating in controlled clinical trials can receive investigational drugs shown in preliminary studies to be promising.


•An orphan drug is any drug developed under the Orphan Drug Act of January 1983 ("ODA"), a federal law concerning rare diseases ("orphan diseases"), defined as diseases affecting fewer than 200,000 people in the United States or low prevalence (prevalence of less than 5 per 10,000 in the community.

•This has been adopted as a subclause of the Food and Drug Administration (FDA) regulations. The granting of orphan drug status is designed to encourage the development of drugs which are necessary but would be prohibitively expensive/un-profitable to develop under normal circumstances.

Orphan Drug


Because medical research and development of drugs to treat such diseases is financially disadvantageous, companies that do so are rewarded with tax reductions and marketing exclusivity (a "monopoly") on that drug for an extended time (seven years post-approval).

The concept behind the ODA is that the longer period of exclusivity will encourage more companies to invest money in research.

Orphan Drug


Under the act many drugs have been developed, including drugs to treat glioma, multiple myeloma, cystic fibrosis, phenylketonuria and snake venom.

In the US, from January 1983 to June 2004, a total of 1,129 different orphan drug designations have been granted by the Office of Orphan Products Development (OOPD) and 249 orphan drugs have received marketing authorization in the US.

In contrast, the decade prior to 1983 saw fewer than ten such products come to market.

Orphan Drug

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