Country Specific Orphan Drug Development and Clinical Submission

Country specific regulatory requirements have been enacted to encourage the development and clinical submission of orphan drugs for off-label and compassionate use regarding patients with life threatening disease. Countries involved in the enactment are Australia, Canada, Germany, Great Britain, France, Netherlands, Switzerland and the US.

Each country participates in ICH. ICH guided, CTD and eCTD clinical submission components, data and documentation presentations, statistical analyses and format are for the most part generic. However, country specific CTD and eCTD clinical submission differences do exist. I strongly recommend early communication with each regulatory agency to ensure country specific CTD and eCTD clinical submission compliance and to agree on a definitive, comprehensive TOC for your orphan drug filing.

A question often asked by pharma pertains to country incentives. Due to the high cost of orphan drug development, yes, there are country specific incentives to encourage the development of orphan drugs. Canada provides incentives for orphan drug development to pharmaceutical companies, clinical investigators, IRBs, interested groups and otherwise. Europe and the US offer the greatest incentives for orphan drug development whereas, Australia and Switzerland provide cooperative incentives with other countries.

In all countries, as always, patient safety is foremost. Orphan drug safety and efficacy filings are reviewed with regulatory rigor by all agencies. Data is assessed for quality, accuracy and integrity irrespective of country. Documentation is reviewed for consistency. High quality data and documentation is standard and expected by FDA and regulatory agencies worldwide.

Emergency Use Authorization of Medical Products - Clinical Submission

The Emergency Use Authorization (EUA) authority recently granted by Congress under Section 564 of the FD&C Act 21 USC 360bbb-3, permits the FDA/FDA Commissioner to authorize the use of an unapproved medical product or an unapproved use of an approved medical product under emergent situations. Under Section 564, the FDA Commissioner may allow emergency medical measures to diagnose, treat and prevent serious or life-threatening diseases or conditions caused by agents, when there are no adequate, approved and available alternatives. The FDA Commissioner, on a case by case basis, will seek advice from DoD, EUWG, ASPR, CDC, NIH, DHS, DVA and other Federal agencies as needed and appropriate.

Clinical Submission Format and Content - Section 564

• paper or electronic
• when paper, FDA recommends that a minimum of 3 copies be provided
• table of contents
• application for authorization may refer to previously submitted data and documentation to FDA
• reviewable form
• risk/benefit statement
• well-organized clinical study reports
• proof of safety and effectiveness
• well-organized nonclinical study reports
• well-organized complete assessments
• well-organized analyses
• well-substantiated interpretations of clinical and nonclinical safety and efficacy findings
• other relevant data and documentation
• clinical source data
• nonclinical laboratory data
• other relevant animal studies
• clinical case report tabulations
• clinical case report forms
• clinical withdrawals
• therapeutic failures
• lost to follow-up data
• adverse event information
• all patients who died during study
• supporting published literature
• supporting references
• certified translations of data and documentation.

Data quality is critical and a must. GCP, GLP, GMP and QC/QA statements, SOPs and plans must accompany the clinical submission. Well-controlled data and documentation will facilitate FDA review and authorization. Quality management of data, documentation, processes, procedures and systems is a must.

A quality controlled discussion of Risks and Benefits must include measures taken to mitigate risk and optimize benefit, document uncertainly and limitations, identify data gaps and provide contraindications.

QC, QC, and QC again, data and documentation to ensure accuracy and consistency with current and previously submitted FDA and other regulatory agency clinical submissions.

Data Quality and Validity in Clinical Trials, Presubmission and Clinical Submission

During development, presubmission and clinical submission, investigational therapies and drugs are tested in a clinical setting with human subjects, providing data and assessments that must be reviewed with regulatory rigor, viewed with public confidence and assessed by pharma and FDA for safety and effectiveness. The importance of informed consent, human subject protection, data integrity and quality in clinical trials and clinical submission has been widely discussed over the last 50 years. It is well accepted that human subjects must not be needlessly exposed to risk in clinical trials that fail to yield data. There is widespread agreement among pharma and FDA that data from clinical trials and clinical submission must be of high quality.

Current processes for assuring data quality and validity were developed individually, by pharma companies, clinical investigators and FDA in response to various problems or crises rather than in a comprehensive quality management framework. Although the current system is successful, it has its flaws and is relatively expensive and time intensive. There is no consensus definition of "quality" as it applies to data from clinical trials and clinical submission. If you doubt that fact, please go to the CFR and check. Many changes pertaining to clinical practice, clinical trials and clinical submission, including the widespread use of automated systems, programming validation, computerized data entry, contract research organizations, increased multinational clinical trials, declarations, WHO and health care delivery systems affect data quality and validity.

Data quality and its validity must be managed, processed and controlled for all phases of clinical development, presubmission and clinical submission data. Approached early and with strict go/no regulatory decisions and data and quality management plans, human subjects are protected and data will be credible, consistent and concise.

Quality Data Pertaining to Clinical Submission - Pharma and FDA

In my experience, greater communication between the pharma industry and FDA is needed when determining quality and adequate clinical submission data handling and cleanup. Pharma and FDA go to great lengths and great expense to ensure data quality. Industry's efforts ensuring clinical submission data quality includes but is not limited to:

• checking source data and documentation in the field
• the use of double data entry systems
• the use of data process cleanup in-process checks
• computerized data quality checks
• the use of standard operating procedures for the review of data listings
• the use of standard operating procedures to identify data outliers
• the use of standard operating procedures to identify data inconsistencies
• the use of standard operating procedures to identify data omission
• the use of standard operating procedures to determine rate of data error
• the use of validation systems to ensure quality data
• the use of extensive documentation pertaining to data handling plans
• the use of extensive quality management data plans
• the use of extensive documentation plans pertaining to data inconsistencies
• how to handle agreements when data changes are implemented.

Pharma and FDA both use qualified and experienced clinical submission individuals and teams in order to verify the quality of data.

• QC
• QA
• Auditors
• Medical Reviewers, Examiners
• Statisticians
• Analysis Programmers.

I am certain there is a duplication of effort between FDA and pharma to ensure clinical submission quality data. During an audit for example, FDA reviews all of the clinical submission data and not just the primary endpoints of safety and efficacy. The perception among pharma is that FDA Medical Reviewers and Examiners do not like to find any errors, omissions, or inconsistencies in clinical submission data, even in minor secondary variables and that the application will lose credibility should minor errors occur. Pharma's view is that there is no acceptable error rate. Not completely true! FDA has been proactive in developing regulations and guidelines to ensure quality data pertaining to clinical submission, electronic data formats, eCTD, CTD formats and backbones, nomenclature and terminology, and other related topics. There are obstacles however to joint efforts by FDA and the industry such as inconsistencies among FDA divisions and pharma in terms of computer hardware and software, computer literacy, review standards, integration standards, analysis standards, other related topics. Greater communication early in presubmission and clinical submission strategies and planning between industry and FDA to develop clinical submission data management and data quality measurements and guidelines for your submittable data would eliminate such data perception and help to manage concerns. Develop a communicative partnership with FDA early to ensure a "same page" approach to your clinical submission data and quality measures.

Preparation of a New Drug Marketing Application for Clinical Submission

Preparation and the size of a New Drug Application (NDA) are determined by the number of clinical trials required to prove a drug's safety and efficacy. A clinical study involving a drug for the treatment of cancer might require only a few hundred subjects, whereas one involving a drug used for the treatment of cardiovascular disease can require more than 10,000 subjects. Other sections of an NDA that require extensive documentation include sections of preclinical pharmacology, toxicology, carcinogenicity, chemistry, manufacturing and controls (CMC) and information pertaining to the eventual drug label.

The scope of presubmission and clinical submission formal meetings between industry pharma sponsors and the FDA are defined in NDA regulation and guidance documents available at FDA or online at fda.gov. Verbal, frequent communication is strongly recommended between the sponsor regulatory functions and review divisions at FDA.

An End of Phase 2 meeting is strongly recommended with FDA. The minutes of the meeting must be documented, agreed and archived at the sponsor location and FDA. As a rule, correspondence with FDA must be periodically reviewed on the path to clinical submission to ensure completeness of submittable requirements. The timing of the End of Phase 2 meeting is strategic to the advancement of sponsor and FDA understanding of the NDA to be filed. Prior to the End of Phase 2 meeting with FDA, a Briefing Document must be prepared by the sponsor. Included in the End of Phase 2 Briefing Document are key considerations pertaining to the overall preclinical and clinical development plans, adverse events of interest, clinical trial study design, statistical analysis plan, a Q&A section pertaining safety and efficacy findings and a proposed overall clinical submission Table of Contents (TOC). Failure to take full advantage of these meetings with FDA will lead to expensive delays. Communicate with FDA often and with transparency.

The key consideration in preparing an NDA is the number of pivotal clinical trials needed to demonstrate safety and efficacy of a new drug in Clinical Phase 3. With a new drug, 2 adequate and well-controlled clinical trials are generally needed to establish the safety and efficacy of the new drug. For oncology or orphan drugs, however, the acceptability of one pivotal clinical trial may be negotiated with FDA. Considerations pertaining to superiority and equivalence clinical trials must be discussed and agreed with FDA as well and will impact the number of subjects included in the overall clinical submission.

Discussion with FDA early in the NDA process will also aid in the determination of time to clinical submission, time to drug approval, time to market, related costs, capacity and resource considerations. Proper tracking of clinical submission requirements become realistic and achievable. Clinical submission leadership and issue management are more focused and transparent.

Presubmission and Clinical Submission Data Collection

A central issue in data collection is how to identify relevant, high-quality data that are readily available for appropriate decision making and to do so in a cost-effective, timely manner, within realistic, projected managed timelines. What is high-quality data? High-quality data refers to data that can be used without further revisions or data that will produce conclusions and interpretations that would be derived from error-free data, data that are accurate, reliable and ready for use. The key to producing such high-quality data is to engineer data quality into the entire preclinical, clinical trial, presubmission and clinical submission process, early in the program.

The factors critical to the successful retrieval and collection of high-quality data begins far upstream from the clinical trial or the start of your FDA Briefing Document and/or halfway through Clinical Phase 3 on your way to clinical submission. High-quality procedures affect all stages of preclinical, clinical trial, presubmission and clinical submission data.

Lets begin with the clinical protocol. The protocol should have:

• clear, specific objectives
• objectives that must be in a testable hypothesis form and design
• well-defined target population with specific criteria
• specific criteria for inclusion and exclusion of study subjects
• a study design that is relatively simple, because complexity introduces error
• relevant, achievable endpoints, primary and secondary
• a detailed schedule of activities and observations
• a process and standard of operation that address steps taken to assure and ensure high-quality data.

High-quality data provides FDA with scientifically valid data, statistically significant, clinically meaningful, data with confidence and credible endpoints and objectives, ready for review and decision. The return on investment when assuring and ensuring high-quality data is immediate and immeasurable.

Performance Management, Clinical Submission Data Governance and Quality

Establishing a standard of operation and a business case for data and clinical submission quality improvement hinges upon the ability to document the pains incurred by identifying errors from day to day. The standard of operation to ensure good quality data and clinical submission are not easy, in fact tedious, but worthwhile and requires leadership and relentless management. The task of segmenting flaws and errors across pharma functions and business units involved with the data and clinical submission is daunting. The impact of data and a clinical submission that lacks quality impacts all pharma and business units from low to high levels of negative perception with FDA and financial projection attributable to "bad data". Reviewing the scale of the data and clinical submission failures based on their corresponding negative regulatory perception, and financial impact will suggest ways to prioritize remediation and "corrective action" and "quality management and change control".

Identifying data and clinical submission flaws, inconsistencies and errors, relies on data quality tools, protocols, processes, procedures and monitoring by an experienced team of quality reviewers and auditors. Data flaws, inconsistencies and errors are not readily seen. So, the process of improving data and clinical submission quality is not an easy task.

However, the challenge in employing the concept of return of investment for justifying the finding of an improvement project to improve quality of data and clinical submission is the ability to monitor, over time, whether the improvements implemented through the project are facilitating positive impacts, for examples, shorter timelines, reduced costs, improved regulatory perception, ease of review, improved credibility with all agencies, enhanced approval perception, reduced time to market, reduced risk management, decreased delays - control surprises.