Saturday, February 27, 2010

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.

Friday, February 26, 2010

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.

Wednesday, February 24, 2010

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.

Saturday, February 20, 2010

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.

Friday, February 19, 2010

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.

Thursday, February 18, 2010

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.

Wednesday, February 17, 2010

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".

Tuesday, February 16, 2010

Preparing a CTD, eCTD Project Planner for your Clinical Submission

In preparing a CTD, eCTD Project Planner for your next Clinical Submission, pharma companies, submission team members, project leaders, managers, regulators and planners must include and integrate communication, correspondence, Q&A, End of Phase 2 Briefing Document discussions, meeting minutes, agreements and commitments, Beginning of Final Marketing Image (FMI) Phase 3 Briefing Document discussions, meeting minutes, agreements and commitments and records of all teleconferences past and current. Communication and resulting deliverables with FDA, now become required regulatory components of the pharma's CTD, eCTD TOC (Table of Contents) and Backbone and must be completed with quality and submitted at the time of filing. If the filing is not complete with FDA requirements as discussed and agreed to with pharma - a RTF, a Refusal to File will be issued when received by FDA. Communications can include but are not limited to CTD, eCTD:

  • content
  • clinical studies
  • statistical analyses
  • file naming conventions
  • navigational QC process
  • folder specifications
  • module numbering (2.7.1, 2.7.2,, conventions
  • module numbering granularity
  • how to present AEs of interest
  • hyperlinking conventions
  • CDISC versions
  • WHO dictionary versions
  • MedDRA versions
  • FDA Guidelines and Guidances at the time of filing
  • how to handle inter-module and intra-module dependencies
  • and otherwise.

It is wise to begin the process of Project Planner Preparation by creating a "generic" project planner and then "customize" the planner in accordance with FDA agreements.

QC all components of the CTD, eCTD clinical submission including hyperlinks, FDA correspondence, module numbering and otherwise to ensure quality, consistency and accurate navigational direction. Navigational QC is an activity that not only "checks" to ensure the accuracy and integrity of your hyperlinks from data to supporting source documents but ensures that the link is "active" and "live" (blue and not black print) when the dossier is submitted to FDA on filing.

Sunday, February 14, 2010

Creating a Project Planner for your eCTD Submission

Pharma companies have awareness and knowledge with respect to "what it takes" to file an eCTD for their drug with FDA. To aid in the overall project planning and eCTD organization and to ensure that the file is complete when you press "send" to FDA - a Project Planner is strongly advised to help manage the overall file and deliverable. Creation of a user friendly, accurate, Project Planner for an eCTD submission, pharma functions, CROs and team members must consider the following "initial" points:

  • task involved
  • resources required
  • capacity required
  • team composite
  • team leadership
  • issue management
  • process and procedure
  • function responsibility
  • CRO responsibility
  • team accountability
  • CRO accountability
  • estimated hours per task
  • estimated number of drafts per task
  • estimated overall timeline per task
  • estimated "start/"stop" dates per task
  • therapeutic indication and claim
  • new chemical entity
  • brand
  • generic
  • typical or atypical eCTD organization, backbone structure
  • special SAEs and how to handle and adjudicate
  • interlinking data and documentation to legacy and previously submitted materials to FDA
  • estimated date of "expected" eCTD filing
  • estimated date of "realistic" eCTD filing
  • correspondence and agreements with FDA pertaining to the eCTD Submission Table of Contents.

Creating a proper Project Planner that realistically addresses task and time is not a one day event. It takes team integration and communication, starting with initial, simple questions and resources while taking into consideration results from preclinical and clinical studies and how to handle serious adverse events of interest.

Above are initial points to consider. More to come...

Thursday, February 11, 2010

Compliant and Correct SOPs for Clinical/Regulatory Trial, Study and Submission

Clinical and regulatory FDA and country regulations are not open to interpretation, however, both guidelines and guidances are negotiable with credible, literature and data based reason and rationale. Once SOPs are written, project leaders must ensure team and company compliance. Adherence to SOPs is critical to data, documentation and company integrity. FDA will not only review the long list of SOPs on audit, but will as well look for a record for proof of implementation, usability, enforcement and a tracking record of compliance throughout the company, project by project, clinical study by clinical study, clinical and regulatory submissions, one by one.

Points to Consider for SOPs:
  • areas where SOPs are useful (times when they are unnecessary)
  • appropriate outline for each SOP
  • what should not be included in company SOPs
  • training on SOPs to ensure team understanding and why the need for the procedure
  • when an SOP needs to be updated and why
  • standards for archiving SOPs
  • FDA access to your SOPs
  • involve FDA in your SOP compliance program - communicate.

Once a year, a pharma company must review/audit SOPs and related procedures in order to assess QC/QA issues and concerns before FDA does so, unannounced and for cause. Proactive, internal pharma audits must be routine and could be prompted much like an alert to generate an annual safety report. In this way, everyone, the team and the company are on board and the attention to SOPs and related activities become a scheduled company practice.

Wednesday, February 10, 2010

Clinical Trials and Neutraceuticals

Clinical trials in humans can be expensive. For neutraceutical clinical trials to be successful and cost-effective, trial objectives must be focused. Animal study data, documentation and results can provide this unique added focus to better enhance the development of a clinical study protocol that is "likely" to generate a positive outcome.

There are several possible approaches for neutraceutical product development. A balanced approach of doing some preclinical testing before, during and after the clinical phase of R&D is prudent and recommended. Remember that each product is different and thus there is no set rule in development. Several "approaches", that safely and conscientiously consider both animal testing and human clinical trials is strongly recommended. The clinical trials can be, for examples, a small pilot clinical study in humans or a proof of concept clinical study in humans. Either would provide useful, hopefully positive outcome information that will be used in future clinical development considerations.

Whether animal or human, testing or clinical study, respectively, remember to apply GLP and GCP as per FDA regulatory rigor and guidance - and quality control all data and documentation early, often and always.

Tuesday, February 9, 2010

Neutraceutical - Animal Testing vs. Human Clinical Trials

Some companies may question the need for spending money on animal testing if they are committed to investing in neutraceutical clinical trials. Perhaps it is less than ethical to test neutraceuticals on animals when human research is equally possible for potentially harmless natural health products. No. There is still plenty of research that is possible only in lab animal testing and not at all in humans. For examples, where there are specific safety concerns for the neutraceutical clinical trial patient/subject and/or where the manufacturing process is likely to alter the ingredient dramatically, it is required by FDA to perform basic, extensive safety testing in animals - before marketing, before human clinical trials.

Even when animal studies are not FDA required, invitro and invivo efficacy and safety studies both offer advantages of screening several ingredients and doses of the same ingredient rapidly and more efficiently in the lab than would be possible in human clinical trials. More importantly, some animal testing models are available that can elucidate mechanisms of actions which are difficult to reveal in simple human neutraceutical clinical trials, Proof of Concept, Phase 1,2 or otherwise. As well, pharmacokinetic and bioavailability markers can be more efficiently and more effectively elucidated in animal studies.

Follow FDA, good laboratory practice, good manufacturing practice and QC when conducting animal studies. If requested by FDA, data and documentation integrity must be met.

Monday, February 8, 2010

Selecting Health Claims for Neutraceutical Clinical Trials

Determining the primary question to be asked in a neutraceutical clinical trial is critical to its success. Ask a wrong question, design the protocol incorrectly and you end up with the wrong answer, no answer, an answer that has no market or regulatory value or even worse, negative data that stays with the neutraceutical for a lifetime.

How does one interpret R&D critical decisions regarding claim selection/definition and design a neutraceutical clinical trial that works?

Simple. Look at what happens in conventional, traditional, drug development - the regulatory process and path provides lessons for planning effective and safe neutraceutical clinical trials. As well, consider all R&D decisions from the point of view of the investigator, regulatory advisement and more importantly, the subject/patient/consumer and sponsor's interests. Follow FDA and pharma standards in clinical design and clinical conduct. Follow good clinical practice and quality control of data and documentation.

Sunday, February 7, 2010

How Natural Products Can Provide the Basis for New Clinical Candidates

Recently, I was asked about preclinical and clinical development and considerations pertaining to phytochemicals, neutraceuticals, natural products and specifically, potential "antitumor properties" and new therapeutics.

Phytochemicals have potent antitumor properties. There is increasing focus of "designer" targeted therapeutic anticancer agents, the broad spectrum of activity of natural products across multiple signaling pathways remains inadequately explored. The chemical diversity, structural complexity, affordability, lack of substantial toxic effects and inherent biologic activity of natural products makes them ideal candidates for new therapeutics. Natural products not only disrupt aberrant signaling pathways leading to cancer but also synergize with chemotherapy and radiotherapy.

Yes, there is a wealth of scientific, research on phytochemicals, nutraceuticals, bacterial and algae secretory by- and end-products as potential, potent therapeutics in cancer, CNS, and otherwise. Much of the early R&D focuses on mechanism of action of key natural products and there is an abundance of early, promising preclinical data for their efficacy as single agents of in combination with standard therapies. Much of the early work in the area of phytochemicals, neutraceuticals and natural "active" products originate at research institutes and academia. Good science, however, preclinical (and clinical) testing, quality controlled testing, regulatory rigor, data and documentation will be needed to build a "true" therapeutic agent. Safety and efficacy must be measured by quality controlled standards as set forth by FDA compliance and regulatory guidance. Product quality and consistency is a must. Consumer or patient/subject safety is the first concern.

Thursday, February 4, 2010

Neutraceutical Clinical Trials and Regulatory Submission

Today, neutraceutical companies are increasingly dedicated to clinical trials and quality-controlled data and outcome endpoints; however, two types of preclinical research - "Formulation & Analytical Development" and "Animal Pharmacology & Toxicology" - are important, although the investment can seem costlier than the results.

Lets discuss F&AD first:

Most companies find a novel compound from countries, India, China, Japan, Poland, Russia, for examples, that they want to market as a neutraceutical globally. The neutraceutical company performs some relevant inhouse laboratory testing and obtain data to substantiate certain health and pharma benefits. The question: Is your neutraceutical ready to make that same claim in most countries? The answer: No.

To be able to market and make the claim worldwide, the finished product must have quality and consistency, and achieve FDA regulatory GMP CMC-like standards. Ingredient certificates of analysis (CoA) provide details on the ingredient itself; however, formulation and production steps ranging from granulation to tablet formation can impact the compound. Further, novel delivery systems and dosage forms also affect an ingredient's bioavailability and stability.

On a global level, innovation in novel neutraceutical dosage forms has been slow, although some actives have been converted into forms suitable for the food and beverage formulation (and FDA).

The net-net - if a finished product is not standardized as it leaves the production lines, demonstrating shelf stability, product consistency, batch to batch, lot to lot, safety and efficacy - your product will not be well accepted by the consumer, the market, the FDA and will not be allowed import/export from country to country.

Quality control of testing claims - data, process and documentation is a must.

Tuesday, February 2, 2010

Is my Neutraceutical Ready for Clinical Trial and Regulatory Submission?

Several neutraceutical clients recently asked me "When will their product be ready for clinical trials and subsequent regulatory submission? The need to know is twofold - one, FDA rigor and requirements, and two, to support marketing claims and increase perception and value of the neutraceutical in the eye of the FDA regulatory reviewer and the product consumer. Clinical trials generate data and documentation that must be collected and cleaned via SOPS for GLP, GMP, GCP and QC. The data must still be quality controlled and quality assured, consistent in statements, patient/subject outcomes and endpoints and marketing claims.

A clinical trial is considered "gold" in the dietary supplement industry yielding immediate marketing value. Other forms of data to support claims for a health ingredient or dietary supplement are not so compelling to the bottom line. Why? Consumers do want to know whether a neutraceutical, and there are many competing for the same claim, works on them and not just in animals, in theory and/or on the "bench". Companies, in the past, relied heavily in the absence of clinical trial data on consumer perception, testimonials and endorsements. However, that does not speak to the product's finished quality.

So, when is your neutraceutical ready for clinical trials?

Preclinical testing is next and prior to clinical testing and trials. The preclinical testing phase is similar to that of a regulated drug, device, biologic, vaccine, etc.
The preclinical testing includes:
  • formulation development
  • analytical development
  • animal pharmacology
  • animal toxicology.

Clinical trials are next in line. At this point, when the preclinical data is collected, QC, summarized and reviewed, and is "deemed" good - the neutraceutical is clinical trial "ready".

Preclinical and Clinical testing results become major factors when considering the acquisition of a neutraceutical product and thus must be quality assured with due diligence review.