Thursday, October 29, 2009

Quality Data Management at Clinical Study Sites

At a clinical study site, who is responsible for quality controlled data, data review and data discrepancy management? Well, the immediate answer is everyone. The responsibility for accurate data lies with a team, each team member responsible for a specific task.
The team members are:
  • Data Manager
  • Quality Data Controller (most often this task is outsourced to consultants)
  • Medical Monitor
  • Data Management Clinical Research Organization (CRO).

The impact of data discrepancy is pervasive, time consuming, laborious and far reaching. Procedural tasks and steps involved in quality data control and review at clinical study sites include:

  • Data Receipt and Entry
  • Data Review
  • Data Quality Control
  • Data Changes
  • Medical Coding
  • Electronic External Vendor Data
  • CRF and DCF Tracking
  • Quality Management
  • SOPs, WIs for Discrepancy Management and Tracking.

It is important to see into the future with respect to accurate data and clinical study databases. At the end of Clinical Phase 2 or beginning Phase 3 Clinical Studies, companies begin to consult with regulatory and clinical submission consultants or companies to create and develop the GIDB - "global integrated database". As a requirement, two GIDBs are developed, one for safety, Phases 1,2,3 and one for efficacy, Phases 2,3. The two GIDBs are developed from the pooling of all required clinical study databases performed during the clinical development and clinical submission time of the drug prior to filing. One discrepant datapoint will impact the data accuracy of thousands of globally integrated SAS programmed statistical tables, listings, graphs and figures. Finding that one discrepant datapoint is like finding a needle in the haystack - not a pretty job, costly and very time consuming, often impacting writing and filing timelines.

How to avoid?

Agree and adhere to process and procedures to ensure quality, accurate data at the clinical study level. Don't wait to find data discrepancies in the GIDB. Use quality data management early in the clinical development and clinical submission plan(s). Avoid data integrity issues early at the clinical study level.

Tuesday, October 27, 2009

Quality Control of Data, Data Review and Discrepancy Management

Standard operating procedures (SOPs) and Work Instructions (WIs) pertaining to data review and discrepancy management are created and used by pharma to ensure that data recorded at the clinical study site is adequately tracked, entered and reviewed within the clinical study database. This data should be systemically and periodically checked for accuracy, consistency and completeness as well as ensuring that errors are investigated and resolved. Another term used to describe data review and discrepancy management procedures are SOPs and WIs outlining "quality control of data".

Quality control of data, data review and discrepancy management will also ensure that documentation exists at the clinical study site.

Quality control of data, data review and discrepancy management ensures that all data discrepancies between the Patient Case Report Form (CRF) and the clinical study database are investigated and resolved.

The SOPs and WIs created and used in pharma for quality control of data, data review and discrepancy management should also include an outline defining metrics for tracking progress, status and quality of the clinical study database.

SOPs and WIs, must include the following parameters:
  • purpose
  • responsibilities
  • procedures
  • documentation
  • edit checks
  • guidelines for handling errors
  • error listings
  • history of data revisions
  • cover memos to cover receipt of error listings
  • metrics
  • tracking
  • and much more.
It is advised that SOPs and WIs themselves be reviewed and agreed upon by the pharma team responsible for the clinical study before one patient data point is collected at a clinical study site and entered into the clinical study database.

Monday, October 26, 2009

Stability/Clinical Studies - 505(b)(2) - Rate-Limiting

Just moments ago, a pharma company called and asked "Are stability and/or clinical studies the rate limiting factor(s) pertaining to FDA clinical submissions using the 505(b)(2) process"?

My advice to the pharma company was as follows and I would like to share this information in this timely post.

All too often, stability studies are the rate-limiting step in the timelines and flow pertaining to ongoing activities of a clinical submission.

The clinical program for many 505(b)(2) drug development programs is often ahead of the formulation development, analytical methods development and up-scale activities. For this reason, some pharma sponsors of the clinical drug submission accept the risk and scale up early in Clinical Phase 1 Study.

However, while in Clinical Phase 1, to mitigate risk, prudent comparability protocols must be included which can answer a lot of questions and help to minimize risk.

Sunday, October 25, 2009

505(b)(2) CMC Role in Clinical Submission

Since the 505(b)(2) clinical submission process is still in its ~first decade with FDA, a question often asked by pharma is "How does CMC (chemistry, manufacturing and controls) play a role in the clinical development program for a 505(b)(2) clinical submission"?

During the 505(b)(2) drug clinical development process, pharma often will change the formulation, components or API (Active Pharmaceutical Ingredient). The impact of any of these changes must be evaluated for impact on the safety, efficacy and tolerance of the proposed drug product. A review of the evolution of the formulation and the data supporting the comparability of the different formulation(s) form the basis for the "Pharmaceutical Development" section of the CTD ( Common Technical Document) clinical submission. A CMC "bridging" study can accomplish these goals.

All sections of the CTD are important, however, CMC is one of the most important and the data must be quality controlled from formulation to formulation, lot to lot, batch to batch, change to change. CMC is the foundation of the drug product.

  • a review of the implications of changes during the clinical development process
  • incorporate comparability protocols at the right point in the program
  • provide a coherent and approvable pharmaceutical clinical development summary for the proposed drug product.

Friday, October 23, 2009

505(b)(2), Importance of a Bridging Study

Since the 505(b)(2) process is relatively new to pharma and in fact, is still evolving at the FDA, one component of the regulatory clinical submission is a must in this process and that is a bridging study.

Pharma often ask, what is a bridging study and why is it pivotal as it pertains to the 505(b)(2) regulatory clinical submission process?

A bridging study, is a Phase 1 study and is used to compare the systemic levels of the drug(s) between the proposed drug product and the reference product. If properly performed and completed, a bridging study allows a pharma company to reference the safety, efficacy and tolerance data that is already known from the original regulatory clinical submission.

In fact, the key pivotal difference between a 505(b)(1) or a 505(b)(2) regulatory clinical submission is exactly the "bridging study".

Always remember, whatever regulatory clinical process used, data integrity and quality controlled data is essential. Therefore, when using the 505(b)(1) or 505(b)(2) regulatory clinical submission process, all data must be quality controlled, concise, accurate, statistically and clinically significant and must be consistent with previously submitted data to regulatory authorities worldwide.

To achieve and ensure quality clinical data, pharma must invest time and a budget to enlist a team of highly experienced clinical data controllers and data managers, "data gate-keepers".

The time and costs involved are minimal when considering and understanding the advantages of data that is quality controlled and pristine. As a result of data integrity, pharma will not have to engage in long question and answer periods pre-filing or post-filing, curious lack of data integrity, under reporting of adverse events and otherwise. The otherwise can lead to regulatory clinical submission and clinical study holds, a RTF and regulatory action letter(s) that are unfavorable to the drug, the data, the pharma and the overall approval.

Remember, always quality control your data.

More About Understanding 505(b)(2)

A question often arises with pharma and that is...Is the 505(b)(2) process and approach equivalent to the drug repositioning process and approach?

The answer is no. These are two different regulatory approaches and processes to leading to drug applications and approvals.

No, the drug repositioning process is where pharma takes drugs that failed clinical programs and make changes in the endpoints of their studies or make changes to the molecule itself in order to get approval.

This is clearly different that the 505(b)(2) process.

Don't be confused - it could result in a RTF or worse - actions that could be taken by FDA.

Thursday, October 22, 2009

Understanding 505(b)(2) and Why

Let us consider for a moment the 505(b)(2) regulatory approval pathway, why you should use it and how it differs from 505(b)(1). What are these two entities? Both are regulatory pathways pertaining to a new drug application (NDA).

The 505(b)(1) process is what the industry is familiar with - this process is used by pharma for new drugs that are new discoveries, new chemical and biologic entities.
The 505(b)(2) process takes drugs that have already been approved and makes small modifications to them often allowed by FDA for significantly advancing patient safety and benefit.
Now, more than ever, the 505(b)(2) process should be used by pharma in times of economic stress and when we are faced with reduced budgets, reduced R&D and shorten timelines.

* The 505(b)(2) process is relatively low risk because the drug has already been proven to be safe.
* It is low cost because there are fewer studies.
* It is also faster due to fewer studies, and if done right, a drug can make it to market in as little as 3 years.

In the economic and competitive climate of today, I strongly suggest that pharma consider the 505(b)(2) process for getting drugs approved and to the market.