Stages In Drug Development And Regulatory Process

Once the sponsor has identified a lead compound, traditionally, the drug development process follows a plan. Most pharmaceutical companies have a drug development plan that is unique to their company based on their own experiences. In general all pharmaceutical companies proceed with development to answer several questions about the drug, i.e., is the drug safe, up to what dose or exposure it is safe, how should the dose be adjusted in certain specific populations or when co-administered with other drugs to have optimized formulation for delivery of the drug.

When a compound has been identified, a Pre-IND (IND-investigational new drug) meeting is occasionally requested with the FDA by sponsors. Sponsor may be a pharmaceutical company or individual investigators. Prior to the meeting, the sponsor usually submits a Pre-IND package. The Pre-IND package may include summary of preclinical data and a concept sheet of a study protocol in order to obtain scientific input from the FDA reviewers regarding the initial IND. The FDA review team consists of a Medical Officer, Clinical Pharmacologist and Pharmacokineticist, Chemist, Pharmacologist/Toxicologist Statistician, and a Microbiologist (depending on the proposed indication). Input requested by the sponsor before the filing of the initial IND usually involves questions regarding appropriate dose and/or dosing regimen selection, safety parameters to be assessed, sampling times (pharmacokinetics and safety), etc., for the "first time in humans" study. Generally, the first study conducted in human volunteers is a clinical pharmacology study to evaluate the safety and pharmacokinetics/ pharmacodynamics of the drug in healthy volunteers or, in some cases, patients. Prior to conducting this first-time-in-humans study, the FDA requires the sponsor to have conducted adequate preclinical studies to support such a study. The sponsor may also request FDA input regarding the development plan for their compound, generally if human data on the drug is available from studies conducted outside the USA. In this case, the OCPB reviewer would review the sponsor's plan and provide additional suggestions, whenever necessary. Examples of OCPB input at the Pre-IND stage regarding overall drug development include formulation development plans, dissolution method development, exploring mechanisms of action, design and conduct of in vitro metabolism studies, clinical pharmacology study designs, identifying potentially useful biomarkers, proof of concept and doseranging studies, exposure-response and/or population pharmacokineticpharmacodynamic assessments, as well as design and dose selection plans for Phase 3 studies. Depending on the complexity of the Pre-IND, the Agency would respond either via a letter or a meeting may be set up with the sponsor.

Protocols for all studies conducted in human volunteers in the United States or that would become part of the NDA have to be submitted to the FDA. Once an IND has been filed FDA assigns a number to the IND. Subsequent study protocols, study reports or sponsor's correspondences have to refer to the IND number.

Once the sponsor has submitted an IND to the FDA, FDA has 30 days to review the submitted protocol for human study. During this review, if there are any concerns about the safety of the subjects to be enrolled in the study, FDA would call the sponsor and place the protocol on clinical hold until the concerns identified by the FDA reviewers are satisfactorily addressed. The IND review process is shown schematically in Fig. 1.

*While sponsor answers any deficiencies

FIGURE 1 The IND review process,

*While sponsor answers any deficiencies

FIGURE 1 The IND review process,

There is keen interest on the part of the pharmaceutical companies to be involved in screening INDs (at the time of the initial IND submission) in which several drugs are screened at the same time and one of the compounds is identified for further development. Further details of this approach can be found in manual of policy and procedures (MAPP) on the FDA website [1].

The drug development stages are not rigid, that is, several phases of early drug development (traditionally called Phase 1 and 2 studies) are generally on going simultaneously. Typically, Phase 1 studies are in healthy volunteers, Phase 2 are studies in small numbers of patients, and Phase 3 are larger clinical trials with adequate number of subjects to determine safety and efficacy of the drug. Phase 1 studies typically include studies related to formulation development, assessment of metabolic pathways, assessment of effects of extrinsic and intrinsic factors such as age, gender, disease, other drugs and food, and assessment of PK—PD. Phase 2 studies are typically dose-ranging and proof of concept studies in a small number of patients who comprise the target population (traditionally called Phase 2A). Assessment of PK-PD is also performed in these studies to help provide an understanding of the doses and dose regimens to be further studied. These studies provide the sponsor as well as the regulatory agencies with the type of knowledge about the drug that is needed to design appropriate confirmatory or definitive large clinical trials in the target patient population (traditionally known as Phase 3 trials). Generally, the FDA needs two positive adequately well controlled Phase 3 trials that support the safety and efficacy of the drug in the target population prior to approval for marketing in the U.S. The overall drug development stages are shown schematically in Fig. 2.

Prior to the start of definitive efficacy or Phase 3 trials, the sponsor usually requests to meet with the FDA at an End-of-Phase 2 meeting. At this meeting, the sponsor discusses with the Agency the information that has been learned about the clinical pharmacology and the limited information obtained in patients about the safety and efficacy of the drug. End-of-Phase

2 meeting discussions with the FDA usually revolve around the decision as to whether the sponsor should proceed to conduct the larger Phase 3 trials and, if so, the appropriate study design for these larger Phase 3 studies. Clinical trial simulations using the in vitro and in vivo data collected from the early phases of development may also aid in optimal design of the Phase

3 trials. The sponsor can request a special protocol assessment [1] for evaluating issues related to the adequacy (e.g., design, conduct, analysis) of certain proposed studies associated with the development of their drug products. Three types of protocols are eligible for this special protocol assessment: (1) animal carcinogenicity protocols, (2) final product stability protocols, and (3) clinical protocols of Phase 3 trails whose data will form

FIGURE 2 Stages in drug development and regulatory process. http://www.

the primary basis for an efficacy claim (if the trials had been discussed at an End-of-Phase 2/pre-Phase 3 meeting or if the review division is aware of the developmental context in which the protocol is being reviewed). The FDA has 45 days to review the protocol and provide scientific/regulatory comments to the sponsor as needed [2]. The guidance recommends that a sponsor submit a protocol intended for special protocol assessment to the Agency at least 90 days prior to anticipated commencement of the study. The protocol should be complete and sufficient time should be allowed to discuss and resolve any issues before the study begins. Special protocol assessments are not to be provided after a study has begun.

There is also a keen interest on the part of the sponsors and the FDA to have a pre-Phase 2 meeting (Phase 2A meeting; i.e., prior to starting the pivotal Phase 2 study in a small set of patients). During this meeting, information available on preclinical studies and Phase 1 studies conducted up to that time can be integrated to assess and discuss Phase 2 protocols. These meetings could provide great opportunity to discuss dosing rationale for the Phase 2 trials, evaluation of appropriate biomarkers, and assessment of exposure-response relationships. There is great interest in these early interactions between the sponsor and the FDA because resources can be used more efficiently and effectively by early communications. There is great opportunity for the sponsor and FDA to identify any limitations in the drug development plan early on, so that all relevant information is available at the time NDA/CTD is submitted to the FDA. These meetings have potential to reduce number of review cycles that some times result, and to produce a better drug product label.

Data and information from all studies conducted during the IND phase are summarized and submitted in one package, i.e., NDA. Prior to submission of the NDA, generally the sponsor requests the FDA for a face-to-face Pre-NDA meeting (usually a few months prior to the submission of the NDA). Issues discussed during this meeting include the content and format of the different sections of the NDA that would be considered "fileable," including issues related to electronic submission of the NDA. At this meeting, assessment is also made if any critical piece essential for regulatory decision-making is missing. The FDA has issued a guidance to the industry on the format and content of electronic submissions that are made to the Agency and are available on the FDA Website.

Once an NDA is submitted to the FDA, the agency assigns an NDA number to the drug. Since not all drugs being investigated as IND become a successful candidate for marketing, it should be noted that NDA number is a different number than an IND number. Once an NDA has been submitted, all correspondence for that NDA should reference that NDA number. FDA has 60 days to file that submitted NDA, or FDA could refuse to file an NDA due to format and content issues or absence of critical piece(s) of information/data needed for the FDA to make a decision on the approvability of the NDA.

Under the Prescription Drug User Fee Act of 1992 (PDUFA), the FDA has defined timeframes applicable to drug application reviews. The FDA usually takes 6 to 10 months from the date of submission of the NDA to make a decision of the acceptability of the application, often referred to as NDA action. This time frame depends on the type of NDA submitted. The FDA gives a priority designation for a product that if approved would be a significant improvement compared to marketed products in the treatment, diagnosis, or prevention of a disease. Evidence of increased effectiveness, elimination, or reduction of treatment related drug reactions, safety, and effectiveness in a new subpopulation, or enhanced patient compliance can demonstrate improvement. All applications not qualifying as priority are classified as standard applications. Priority applications are reviewed within six months, where as standard applications have a 10-month review clock. A decision regarding the assignment of a standard or a priority rating to the application is made before the 60 day filing of the NDA.

There are certain types of drug approval processes that facilitate the development and expedite the review of the new drugs that are intended to treat serious life threatening conditions and to demonstrate the potential as treatment for an unmet medical need. Some of these programs are the accelerated drug approval/fast track programs or rolling submissions. The accelerated drug approval program (Subpart H) is a highly specialized mechanism for speeding the development/review of drugs that promise significant benefit over existing therapy for serious or life-threatening illnesses like AIDS, cancer, Parkinson's disease etc., and for a condition for which no therapy exists. This program involves the modification of the criteria on which the approval is based on. It allows for approval to be based on a surrogate endpoint or an effect on a clinical end point other than survival or irreversible morbidity. Under such circumstances, the program may require appropriate post approval studies to validate the surrogate endpoint or otherwise confirm the effect on a valid clinical endpoint.

When certain sections of an application are accepted by the Agency prior to the receipt of the complete application, the submissions are referred to as rolling NDA submissions (i.e., pre-submission of pharm-tox reports, clinical study reports, and even data summaries and listings from the first of two or more pivotal trials). Sponsors of designated fast track products can request this type of submission by submitting certain completed portions of an NDA prior to submitting the other sections of the application. In such cases the sponsor is required to provide a schedule for submitting the information necessary to make the NDA submission complete. Further details of these programs can be found under Regulatory Guidance and Mapp (Manual of Policy and Procedure) on the FDA website [1, 3].

Sometimes there is a need for either an Advisory Committee Meeting or a face-to-face meeting with the sponsor to discuss issues that arise during the NDA review process. Once the NDA is submitted, pivotal study sites are identified and inspected for good clinical practices (GCP) and good laboratory practices (GLP) compliance by the Office of Compliance. An NDA action is taken after obtaining results from the inspection of the study site. The action could result in the approval or non-approval of an NDA, or in an approvable NDA. An approvable NDA implies that the information that has been reviewed by the FDA appears to be an acceptable data; however, some additional information is needed to approve the product for marketing in the United States. This could involve collection of additional data, data re-analysis or negotiation of labeling language. The overall NDA review process is shown schematically in Fig. 3.

Table 1 summarizes the type of studies that are typically part of the clinical pharmacology and biopharmaceutics plan for a new drug, and Table 2 gives an example of how all of the clinical pharmacology and biopharmaceutics information can be summarized concisely. Readers are

FIGURE 3 NDA review process,

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