Budgeting Impact on Superfluous Clinical Trial Data

In the previous post, we spoke about superfluous collection of clinical trial data and its impact on clinical trial integrity and quality, extra unnecessary data, increased patient dropouts, increased costs, missed timelines, under-resourced departments, etc. The remedy remember is to involve team players and biostatisticians early on the clinical and regulatory path to design a clear-cut protocol with achievable clinical outcomes that are medically meaningful and statistically significant. In other words, design a SAP, statistical analysis plan, that is precise.

Budgeting - patient recruitment can also help in the reducing unnecessary data collection. At the outset of patient recruitment, pharma must first determine a number of factors about the clinical trial that will influence cost, time and yes, data. The budget, the number of patients recruited and the amount of patient data collected are closely linked. All 3 will be influenced by:

• how many patients are needed for the clinical trial
• how many patients must be screened to randomize the required number of patients
• how many investigator sites will be involved in the clinical study and where will they be located
• what percentage of patients is the investigator site capable of recruiting and what percentage must be recruited by the pharma, CRO
• is this a pivotal clinical trial seeking results for a new drug application (NDA)
• how experienced is the pharma at recruiting patients in the therapeutic area in question
• how long is the clinical trial expected to last
• how restrictive are the patient inclusion/exclusion criteria outlined in the clinical study protocol
• are there alternative therapies already on the market.

Unnecessary Clinical Trial Data Leads to Extra Time and Cost

Oftentimes, clinical trial teams collect, clean and analyze 5 to 10 or more pages of excess clinical trial data that is never used in the final clinical trial or study reports. Moving too much data through the entire clinical trial process - including collection, data entry, data storage, querying, statistical analysis, report writing and review - leads to extensive increases in clinical trial timelines and increases the probability of data errors. Failing to narrow down the target data for clinical trials early in the study planning phase causes trials to last longer than they would otherwise have to and as well, increases the length of time to clean and quality control and quality audit the clinical trial database. Often, the number of patient visits are too numerous and too long. Thus a poor clinical trial and protocol design, will inevitably lead to more patient dropouts, erroneous data, more patient withdrawals, increased patient non-compliance and failures to follow-up. Quality control and quality audit time increases and leads to unnecessary increases in clinical trial costs, CRO, Investigator, all outsourced and otherwise, not to mention time of employees to monitor clinical trial progress, performance and status. Recent reviewed reports on this subject, estimate the time wasted on the unnecessary data collected and related activities exceeds 2-3 months when all of the additional work and rework, quality control, cleaning and quality audit are combined. As well, may seriously jeopardize the integrity of clinical trial data collected. Solution: Working with biostatisticians early in the clinical trial protocol set up, planning and design to eliminate the collection of extra, unnecessary clinical trial data. Simple. Take the team approach.

Outsourced Manufacturing Suppliers and Quality Regulatory Audits

Recently I was asked by pharma, how can we ensure that outsourced suppliers are manufacturing product in accordance and compliance with FDA regulations. FDA regulations are clear, whether for drug, device, biologic, vaccine, other, pharma is ultimately responsible for the quality of their product. FDA has new regulations pertaining to quality manufacturing activities (and a new Commissioner) and thus, the industry will be scrutinzed regarding increased regulatory, quality rigor, focused on enforcement of high standards of manufacturing and operations.

What can you investigate before choosing your outsourced supplier for your manufacturing needs:

• audit and evaluate business practices and standard of operations
• audit and evaluate quality, management and manufacturing systems, in process checks
• audit and ask about records, procedures, validation, maintenance, calibration, traceability, processes
• audit and review procedures that address actions for non-conforming product and standard deviation
• audit and investigate history of product release, training, customer track record, pharma satisfaction, FDA satisfaction/correspondence, complaint actions and responses
• audit contracts.

Quality should not be predicted. Quality should be evident by audit. Choose your outsourced manufacturer by audit to ensure quality and adherence to FDA regulations and guidance.

Pros and Cons to Clinical Partnerships and Metric Model Selection

In the last 5 years and most probably due to the vast number of pharma M&A, easily measured clinical conduct, operations and submission resource solutions have been lost in the chaos. For example, several pharma believe that the CEO of the company must be involved in and focused on the life cycle of the clinical trial and clinical submission. No. Many pharma use elaborate tactical and strategic sourcing plans and metric model selection processes to resource their clinical trial and clinical submission needs and requirements. No. A number of pharma fall to strategic partnerships to reduce their resourcing and outsourcing burdens. No. Many pharma tend to follow complicated collaborative schemes by applying multidimensional performance metrics for improved clinical trial and clinical submission management indices. No. Pharma companies are trying to learn how to avoid 483 observations regarding FDA oversight and resultant compliance and deviation issues. No. Bridging the gap with so many strategic partners can only provide more chaos, create vacuums, isolate people and data, reduce ease of communication.

Classic drug, device, technology development is simple when processes and procedures are clearly mapped out in detail from start to finish and resourced properly by understanding how long it takes to create a SAS program, write a clinical summary of integrated safety and efficacy, review a safety narrative, prepare a patient profile, quality-control (QC) a clinical study report, develop a global integrated database, publish a submission-ready document - only then can pharma accurately and effectively manage resource responsibilities, start, stop dates and accountability, that will lead to a successful, compliant clinical trial and clinical submission.

Keep it Simple. Follow the regulation and guidance. Don't get fooled by elegant ways to short-cut the system or quality. Do it right the first time. Keep the team hands-on, communicate clearly and often, lead the team, manage the issues. Walk the halls.

Strategic Partnerships in Clinical Trials and Clinical Submissions

Often pharma companies are faced with a huge pipeline of drugs, devices and technologies to develop after M&A. Often after or during a M&A, and as a result of the M&A, there is not enough in-house employees or employees with the specific expertise required to develop and conduct clinical trials and/or prepare and submit a clinical submission to FDA and/or regulatory agencies worldwide. There is no shortage of CROs who participate in resourcing outsourcing needs or even "partner" with the pharma company. These strategic partnership agreements between pharma and the CRO are often created and do benefit both the pharma sponsor and the incoming CRO. The selection of a CRO and more importantly a CRO strategic partner is no an easy process. In fact, if performed correctly, the process of selection very much resembles an audit and takes much time and effort. However, the time and effort spent on selecting a fit for your clinical trial and clinical submission is critical and unmeasurable in value. To ensure a fit with pharma and the CRO is terms of vision, one needs to look closely at CRO metrics such as "pace and intensity, quality and met timelines". Look at the track record of "success" in the particular therapeutic field of development and submission for starters.

Recently, I read a brief summary describing the monetary consequences of not choosing the appropriate CRO or CRO partner. Internal resource burden of not outsourcing efficiently can result in 50% more FTEs. Having to repeat a Phase 2 clinical trial due to erroneous, incomplete, data can amount to $10-$20M. Selecting the wrong clinical partner for your clinical Phase 3 trial will cost the pharma partner $5-$10M. Loss of valuable time to market due to clinical trial delays can result in an extra unnecessary expenditure of $10-$50M. Therefore, selecting the the best partner for your clinical trial and clinical submission is critical and worth due diligence, audit and investigation.

More to come pertaining to the selection of a clinical trial and clinical submission partner.

FDA Expedited Regulatory Submission Review of Device or Device with Drug Product

FDA from time to time, publishes nonbinding recommendations for device, technology, drug or otherwise, for expedited regulatory review in an effort to benefit patients who fall into a unmet medical emergent, urgent need for therapy, in need of new breakthrough technology and serves the best interest of patients in life-threatening situations or irreversible debilitating disease or condition.

Breakthrough technologies must be demonstrated to lead to a clinical improvement in the treatment or diagnosis of the life-threatening or irreversibility debilitating condition.

The device must provide for a clinically important earlier or more accurate diagnosis or offer important therapeutic advantages in safety and/or effectiveness over existing alternatives. For examples:

• superiority over current treatments for advantages on serious outcomes (e.g., morbidity)
• ability to provide clinical benefit for those patients unable to tolerate current treatment
• ability to provide a clinical benefit without the serious side effects associated with current treatments.

The availability of the device must be in the best interest for patients and that is, the device provides a specific public health benefit or meets the need of a well-defined patient population.

All provisions may also apply to a device that was designed or modified to address an unanticipated serious failure occurring in a critical component of an approved device for which there a no alternatives or for which alternative treatment would entail substantial risk of morbidity for the patient.

FDA is open to demonstrations of real benefit for the safety and well-being of patients who have compassionate and life-threatening pleas. Regulatory submission documentation and dossier for the device, device with drug must be pristine, demonstrate clinically meaningful and statistically significant benefit, quality-controlled data and provide a remarkable and superior benefit/risk statement.

Devices Appropriate for Expedited FDA Regulatory Review

FDA considers a device or combination product containing a device appropriate for expedited regulatory review if the device or combination product:

1. is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition and
2. addresses an unmet medical need, as demonstrated by one of the following:

• the device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology
• no approved alternative treatment or means of diagnosis exists
• the device offers significant, clinically meaningful advantages over existing approved alternative treatments
• the availability of the device is in the best interest of patients.

Under "special " considerations, pharma manufacturers who are working with a Federal Agency in the development of medical devices to address a national security issue should include a letter in the premarket regulatory submission from the Federal Agency, likely, Department of Defense, Department of Homeland Defense, identifying the specific device or device type and indicating that commercial availability is of particular importance to our national security. The letter of course, must be printed on official agency letterhead and signed by an individual with appropriate authority for making the request.

More information to come pertaining to the definition of "breakthrough", "clinically significant therapeutic advantages" and "public health benefit on device availability".