Pharma Expansions, Mergers and Acquisitions - Clinical Operations - De-centralization vs. Centralization

Recently and due to expansions, mergers and acquisitions, I was approached by pharma to assess and develop and implement a more centralized clinical operations function. With a pipeline of promising new products and rapid growth, the pharma's clinical operations organization expanded considerably and rapidly, becoming fragmented. This fragmentation generated operational inefficiencies and lethargic performance due to several business models existing under the same roof, serious communication issues, a loss of focused leadership, a de-centralized team, duplication of resources, capacity, responsibilities and accountabilities. Certainly, in addition, lost timelines, target dates and quality were sacrificed in the expansion.

This is now a common issue throughout the pharma industry with current expansions, mergers and acquisitions. The assessment required the development and implementation of a new internal and external re-structure, plan and operational process moving forward. The new structure included a good deal of re-work pertaining to, but not limited to, internal and external functions, outsourced resources, leadership, management and strategic planning.

As the pharma company prepared for its first clinical and regulatory submission to FDA, EMEA, and product launch, there was a great need to identify, process and communication bottlenecks and determine which of its functions required the most improvement in a limited time. Short term, long term objectives. Gaps and stumbling blocks in the pharma company's processes were identified and worked through to improve the pharma company's clinical trials operations, performance and quality, good clinical practice. In-depth assessments, process and quality forensics, data and documentation audits focused on short and long term objectives, outlining the best practices. Opportunities for improvement were assessed and implemented. The implementation plan was agreed upon by all functions, all teams, all CROs, inhouse and outsourced, external. An implementation guide was developed for the pharma and was critical to the execution of the prioritized recommendations. Bridging the gap between corporate leaders and operational staff, team and functions was the main key to improvement. Re-build and revise, budgets, processes, standards of operations, plans, optimize alliances, internal and outsources and maximize efficiency and leadership. Key short term objectives.

• Optimize focus groups of operational staff, CRAs, CTMs to solve operational problems as they arise.
• Provide a no consequences feedback mechanism from operational staff to corporate leadership thereby opening communication.
• Perform a where, when, who and why responsibility trail and train to clarify roles and decision makers.

Phase 4 Clinical Research - Increasing Importance to "Buyers"

Phase 4 clinical research data provides key groups and decision makers with important information pertaining to the safety and efficacy of a drug once approved by FDA. Data and documentation must find its way to physicians, insurance providers, buyers, opinion leaders, pharma sales force and of course FDA, for purposes of review, promotion, education, prescribing, retail, regulatory rigor, patient safety.

Phase 4 clinical research has increasing importance for distributors when helping consumers understand product labels, PDR, package inserts, product brochures. With increasing consumer demand for drugs, natural products, and otherwise, there is more need for research and in-store nutrition knowledge within the retail sector. Sales, marketeers and retailers must be well informed about the products they distribute and sell. Retailers have an important role in explaining nutrition product labels to consumers. This presents opportunity for natural product suppliers to utilize clinical research, in conjunction with market and outcomes research to train and educate their distributors using their product's clinical trial data and documentation.

Opportunities such a advertising displays, promotional items, leaflets, brochures, manuals, pamphlets, videos, infomercials, and otherwise must be used by distributors so they can market to their consumers. Phase 4 clinical data and documentation must be quality controlled and collected with regulatory rigor and good clinical practice. All promotional information whatever form of media used to educate, disseminate and/or train, must also be quality-reviewed and quality-controlled. Phase 4 clinical research must be transcribed, translated, presented and summarized with quality control, consistency, version control, precision, clarity, consistency of claim, statement, storyline and accuracy. Engage experts in quality. Engage gate-keepers who ensure version control of didactic, Phase 4 clinical research, promotional materials, data and documentation worldwide.

The Importance of the Sales Team - The Importance of Quality and Communicated Phase 4 Clinical Research

Key target groups must be involved with drug safety and efficacy throughout the life cycle of the drug once approved by FDA. Key groups are physicians, providers, opinion leaders, sales, buyers and FDA. Sales Team - Although not a target group, the sales force must nonetheless be a priority for any pharma engaging in direct to physician sales. The sales team acts as the spokesperson between the pharma/product and the physicians. Pharma must proactively and continuously keep members of the sales force educated on the benefits (and risks) of the product. The degree of success of the pharma sales team directly influences the revenue, ROI, generated for the pharma and the longevity of the brand in the market.

Sales and marketing groups must be proactively informed with consistent, up to date, quality-controlled, clinical trial data and documentation. Global ongoing Phase 4 clinical trials generate global data and documentation. The data and documentation must be organized and managed by experts who serve as gate-keepers for data and documentation version control. Gate-keepers, who are quality control experts in compliance, quality and regulation, ensure quality review and presentation of accurate and adequate, safety and efficacy data and documentation and must interact with marketeers worldwide. Phase 4 clinical research is of course, worldwide.

Remember, every communication to the physician, the patient, the key groups...abstract, newsletter, data, database, clinical protocol, Phase 4 clinical submission, CSR, CTR, expedited safety report, periodic safety update report, annual report, safety narratives and otherwise must be in compliance with regulatory rigor and FDA, Code of Federal Register (CFR) and must be consistent in data, storyline, presentation, statement, claim, product label, previously submitted clinical submission dossiers and must demonstrate clinical, therapeutic application and statistical significance, worldwide. Monitor the clinical trials, monitor the monitors, monitor the quality of the data, review all source documents, follow good clinical practice. Engage experts.

Phase 4 Clinical Research - The Role of Key Opinion Leaders

Phase 4 Clinical research data provides current information pertaining to an FDA approved drug in the marketplace and in a real life setting. The drug, once approved by FDA, must be monitored with rigor for safety and efficacy by pharma throughout the life cycle of the drug product. Pharma especially, must closely monitor and adhere to safety surveillance and risk marketing plans agreed to with FDA before granting approval to market. In earlier posts, we spoke of the contribution of physicians and health care providers and their role in the dissemination of clinical research data and documentation to key target groups. Key Opinion Leaders, another target group, as well, have a unique position in the dissemination of clinical data and documentation to interested parties.

Effectively marketed clinical data to Key Opinion Leaders (KOLs) is a critical huge factor in gaining full product support in the marketing arena. KOLs are expert physicians who have influence over medical practice. KOLs are sought out groups of experts who set the pace for industry trends. KOLs will share a wealth of information and insight ranging from clinical science to advertising concepts and provide highly credible exposure for a product in the medical community through speaking engagements, published articles in medical journals and general practice. Engage KOLs in market research and medical symposiums. Engage KOLs with the latest clinical research early and throughout the product's life cycle. Engaging KOLs early in marketing practice and plans will ensure pharma with an invaluable feedback and insight throughout the life of the product and thus increased marketing exposure in clinical practice. KOLs are essential to quality. KOLs are essential to ROI.

Responsibility to Disseminate Clinical Research and Educate Key Target Groups

Clinical research data from Clinical Trial Phases 1, 2, 3 and 4 provides the most up to date scientific objectives and prescribing information for an approved drug. Pharma must educate all key groups who have a vested interest in the well being of the patient throughout the life cycle of the drug. Dissemination of information to at least the following primary constituents is a must.

• Health Care Physicians
• Health Care Provider's - A provider's responsibility is to provide health care that is effective, affordable and satisfactory to as many people/patients as possible. When new products have entered the market, health care providers are primarily concerned with clinical research that demonstrates information pertaining to patient tolerability, safety and effectiveness. Clinical trial research is paramount for adequate development of "friendly and patient focused" health plans. In today's medical culture where the paradigm has shifted from the physician to the patient, health care plan companies see the need to become more patient-oriented. This presents huge opportunities for pharma companies to work with in-house and external clinical researchers and spearhead additional types of clinical research.
• Buyers, Consumers, Distributors
• Key Opinion Leaders
• Sales and Marketing
• FDA.

Responsibility to Disseminate Clinical Research and Educate Key Target Groups

Questions often asked - Can clinical research be used to disseminate and educate key target groups? Who is responsible for the dissemination of product information once the drug is approved by FDA? The answers are yes and the responsibility of pharma primarily as per post-marketing commitment plans with FDA, respectively.

It is the responsibility of pharma to continue to investigate, elucidate and clarify safety and efficacy benefits and risks for the life cycle of the drug once approved by FDA. Clinical research provides the most up to date scientific intelligence pertaining to drug mechanism of action, safety, tolerability and effectiveness. Clinical research assists key target groups and decision-makers, physicians, health care agencies, health care providers, health care payers, patients, buyers, M&A, key and expert opinion leaders, shareholders, stockholders, sales and marketing, FDA and regulatory agencies worldwide and otherwise to make clinically and meaningful decisions.

It is essential for the pharma industry to educate and disseminate, well monitored, well audited, integrated, summarized quality data and documentation to relevant and appropriate communities and interested parties.

• Physicians - It is ideal, especially for pharma companies that health care professionals base their prescribing decisions on supporting evidence provided by quality clinical submission, regulatory approved data, statements and documentation. Prescribing code reinforces that professional exchanges with the medical community are designed to benefit patients and medical practice. The more robust the clinical evidence, data and documentation, the better the case for that drug to be prescribed. Now more than ever, during the post approval period and life cycle of the drug, there is, as well, a good opportunity to more define the product's ROI - return on investment, with continued clinical research.

More to come...

• Health Care
• Health Care Payers
• Key Opinion Leaders
• Sales and Marketing
• Buyers, Patients, Distributors, Consumers
• FDA.

The Importance of Phase 4 Clinical Research

Often the question arises - What is the importance of Phase 4 clinical research? In an industry, that is heavily regulated and scrutinized, pharmaceutical brands must not only go through Clinical Study Phases 1, 2 and 3 to validate the drug's safety and tolerability, but as well, testing of the product to monitor its safety and effectiveness in a real-world setting and after the product is approved for marketing is a must and is required by FDA.

Post-marketing clinical research trials, used interchangeably with Phase 4 testing, is a phase that takes place after a product is available on the market for public use and is subsequently used to track a product's safety and tolerability in a real-world setting. Marketers in the pharma industry know that the clinical research needed to market and sell a drug product is quite different than research needed to gain FDA approval.

In addition to post-marketing surveillance, Phase 4 clinical studies are also helpful in developing a marketing strategy for a product. In fact, post-marketing research gives insight into questions and concerns raised earlier in Pre-Clinical and Clinical Phases 1,2 and 3. Not only does Phase 4 research allow pharma companies to monitor for real-time effectiveness, long-term safety and tolerability, but it may also give rise to evidence for possible new indications, new markets for which the drug product had not been initially approved. The value of conducting post-marketing clinical research is required by FDA to continue to ensure patient safety post-submission, post-approval, post-marketing. In my opinion and to ensure data with integrity, monitoring post-marketing clinical studies requires quality control, good clinical practice, quality standards of conduct and operation as well as regulatory rigor. Monitor the monitors. QC/QA the data.

The Necessity of Phase 4 Clinical Trials

Is there a necessity for Phase 4 Clinical Research and Clinical Trials? Of course, the answer is yes. Before drugs are marketed, drugs are considered clinical candidates. During Clinical Phases 1, 2, and 3, pharma studies are designed to test, determine and validate the overall efficacy and safety of the drug. Clinical Phase 1, 2 and 3 processes can take many years, filled with trials and errors. If FDA's action is to approve the drug after advisement, review and regulatory rigor, the pharma company is required to ensure that unanswered questions, viewed by FDA to be time sensitive, are answered.

Unanswered questions, for examples...

• How safe and effective is the drug's use in a diseased population
• How safe and effective is the drug's use in a compromised patient
• How safe and effective is the drug's use in special patient populations
• How safe and effective is the drug's use in a diseased population with varying degrees of illness, mild, moderate, life-threatening
• How safe and effective is the drug when used by a patient with more than one illness
• How safe and effective is the drug when taking multiple drugs
• How does the drug product compare in safety, efficacy and tolerability with other products in its class
• What are the risks of the drug
• What are the benefits of the drug
• Do the benefits outweigh the risks.

A comprehensive Phase 4 post-marketing safety surveillance plan/risk management plan developed by pharma and agreed with FDA is the essence of the Phase 4 clinical program. Phase 4 respective plans are developed to answer questions pertaining to drug performance, safety, efficacy and use. Data from Phase 4 clinical trials is essential to:

• Pharma and FDA in order to adequately evaluate patient safety post approval
• Pharma who face the daily challenges of answering post-approval questions
• FDA who closely monitors safety AE and SAE reporting during the post-marketing period.

More to come...

Post-Marketing Phase 4 Clinical Trials - Pharmaceuticals vs Natural Products

Recently, a number of questions arose by pharma and industry pertaining to the similarities and/or differences between post-marketing (Phase 4) clinical trials comparing pharmaceuticals vs natural products. First, the main similarity is that all have a definite health benefit and have therapeutic value. Secondly, FDA's "current" approval process is very different for natural products, there is no Phase 1-3 clinical program per se, until of course, FDA "knocks" on your door. It is no surprise that Phase 4, post-marketing clinical research and clinical trials have become the fastest growing area of clinical research today. The stakeholders for the natural products industry remains the same as for pharma, such as but not limited to: consumers, patients, homeopathic, herbal practitioners, physicians, complimentary health professionals, naturophilics, holistics, homeopathics and buyers, with slight differences in one category over the other. Each of these groups must complete clinical Phase 4 trials, with good clinical practice, industry standards of operation, quality control and quality assurance and compliance with FDA regulations. Post-marketing Phase 4 requirements are the same in terms of quality, statistical significance and clinically meaningful results. Data is collected and integrated, summarized, presented, submitted, filed and reviewed by FDA. FDA will act on approvals, approvables or non-approvals. The same process holds true for dietary supplements, cosmeceuticals and neutraceuticals with respect to Phase 4 clinical and regulatory submissions to FDA. In a growing industry that is saturated with "natural" products, clinical research/clinical Phase 4 trials becomes the defining factor in distinguishing a product from its competition, strategically positioning the product against the standard and enhancing the product's characteristics, benefits, attributes and health claims among others.

How to proceed?

• Differentiate your product from others
• Enhance product sustainability
• Increase ROI
• Set and achieve workable and attainable clinical goals, endpoints and objectives
• Attract consumer and patients by enhanced, quality controlled health claims
• "Right" - position the product
• Enhance the brand
• Proceed with data integrity and consistency
• Proceed with data consistency
• Ensure FDA compliance and agreement
• Ensure FDA compliance with guidelines and regulations
• Ensure Good Clinical Practice
• Ensure Good Manufacturing Practice
• Ensure "correctness" and validity of health claims and benefits
• Expect FDA.

Early Stage Drug and Device Development - It takes a team to win!

Implementation of early stage integration of sales and marketing goals with clinical and regulatory groups early in the development of the drug or device is essential. Implementation of early stage integration of marketing and clinical structures, clinical/regulatory submission teams, whether through new product development groups, joint project management teams, formal communication processes, co-governed portfolio management authorities or otherwise is critical.

In these arrangements, there are definite benefits from some form of pooling of ideas. While portfolio groups and multi-faceted oversight can be challenging, there is ROI. One group, must be in control of the process and although many pharma companies choose sales and marketing to carry the ball, the development must be a function of clinical, regulatory and project teams.

Each group's level of strategic influence will vary in the process, however, the important point is that all functions and strategic groups, are heard. Group input becomes a part of the overall development process which inevitably and favorably impacts costs, timelines, resources, capacity and improves quality, quality control and quality assurance.

Enable group communication, knowledge sharing, coordination and "gate-keeping" of information. It takes a team to win. Group communication unites people from different backgrounds in the development process. Groups with diverse experiences and expertise come together to achieve common goals and objectives on time and cost-effectively.

Sound "gate-keeper" activities and "hands-on" project direction and management early on allows teams and groups to navigate go/no go product profile decisions more effectively. The benefits are real and provides a clearer overall picture of clinical and commercial assets and outlooks, especially when clinical candidates are being developed in parallel.

Time Frames of SAE Reporting - Clinical Trials

SAE (Serious Adverse Event) Reporting is critical to patient safety and is required by FDA while a drug is under clinical research and development. SAE reporting and time frames are required by FDA and are reviewed and approved by an independent Investigational Review Board (IRB) for each clinical study protocol. SAE Reporting and agreed time frames must be in compliance with FDA patient safety guidelines and developed for each investigational drug, device, dosing regimen and therapeutic indication under study. For example -

Pre-dosing:

• Events occurring before taking study drug are not reportable unless related to study procedures.

Dosing during study:

• All SAEs are reportable.

Post-dosing (regardless of the drug relationship):

• All SAEs are reportable from the first dose of the study drug until 28 days following discontinuance of the study drug regardless of relationship to the drug.

Post-dosing (drug related):

• All SAEs that are believed to be drug related must be reported regardless of time elapsed since the last study drug dose, even if the clinical trial is stopped or on clinical hold.

Pregnancy reporting:

• Dosing during study/post-dosing - Pregnancy occurring in patients treated with the study drug or which occurs up to 90 days after the last dose of the study drug are reportable as SAEs.
• Pregnancy occurring in the female partner of a male patient in a clinical trial whose last dose of study drug was within 90 days of conception is also reportable.

Expedited SAE reporting includes:

• AEs which are serious and unexpected and classified as drug related qualify for expedited reporting to the FDA.
• Information that may influence the benefit/risk assessment of a study drug or that would be sufficient to consider changes in the study drug regimen, administration or in the overall conduct of the clinical drug investigation and protocol design.

As always, early planning, early reporting is a must with SAEs.

CTD Clinical Submission of Phase 2-3 Trial Data

Phase 2 - 3 clinical safety data presentation, pooling and integration strategies are developed by the clinical submission team and illustrated in your SAP, statistical analysis plan, for all therapeutic indications to be filed in your clinical submission. On an average, a Phase 2 - 3 clinical program consists of 10-15 studies, conducted simultaneously in the US, Europe, rest of world and are designed to "flush" out AEs, SAEs, dosing regimen, safety and efficacy. The Phase 2 - 3 clinical program reflects the "final marketing image" of the drug to be filed. Phase 2 - 3 integrated safety data, is the clinically meaningful information used to develop the "prescribing" label, package insert, information for the PDR (Physician's Desk Reference) for the drug under investigation. The process of integration, pooling strategy and presentation methodologies for Phase 2 - 3 safety data is analogous and linked to your Phase 1 SAP.

For example, a Phase 2 - 3 clinical program consists of 13 clinical trials - a common pooling strategy for safety data would be as follows -

• Pool 1 - 5 clinical studies, double-blind, placebo-controlled, fixed-dose (primary therapeutic indication)
• Pool 2 - 3 open-label, long-term exposure studies - (primary therapeutic indication)
• Pool 3 - 3 double-blind, placebo-controlled, forced-dose titration studies (primary therapeutic indication)
• Pool 4 - 2 special studies, in a different, but related therapeutic indication
• Pool 5 - 10 double-blind, placebo-controlled studies, regardless of indication, pooling of Pools 1, 3 and 4.
• 5 Pools - 13 Phase 2 - 3 clinical studies.

The integrated analyses of clinical safety data includes Adverse Events, clinical laboratory evaluations, vitals signs, physical findings and other observations related to safety and safety in special groups and situations. In the integrated analysis, the Medical Dictionary for Regulatory Activities (MedDRA), is used to classify all Treatment Emergent Serious Events (TEAEs), reported by System Organ Class (SOC) and Preferred Term (PT) as per FDA regulations and data compliance guidelines.

A separate safety integrated and pooled database for Phase 1, 2, 3 Clinical Pharmacology data is submitted to FDA as well at the time of filing. Likewise, statistical analyses, integration and pooling rigor and strategies are developed for the best presentation and evaluation of pharmacology safety data for clinical submission and FDA review.

Clinical/Regulatory CTD Submission - Integrated Pooling of Phase 1 Safety Data

In order to identify all potential safety signals in your Phase 1 clinical trial program for clinical/regulatory submission, an integrated analysis of the safety data from all studies is recommended. The FDA most definitely recommends "some pooling across all Phase 1 Clinical Studies". There are several approaches. The most common approach is a pooling of single dose exposure trials and a second pooling for multiple dose exposure trials. Due to the heterogeneity of Phase 1 studies often pharma will choose to only pool "like" clinical studies and present fixed dose, parallel group, dose escalation, crossover design, drug-drug and special populations separately, by individual study.

For example, safety data is available at the time of clinical/regulatory submission for 22 completed Phase 1 trials -

• 7 studies were single dose studies - integrated Pool 1
• 8 studies were multiple dose studies - integrated Pool 2
• 5 studies were drug-drug - presented individually
• 2 studies were special populations - presented individually
• 15 studies would then be integrated
• 7 studies presented individually.

Not advised and definitely not advised without FDA communication and consensus. If the Phase 1 clinical program consists of 22 clinical trials, FDA will want all studies pooled. Why? To ensure that all AEs are captured and reported. To ensure patient safety. To ensure a benign safety profile, especially if the drug is a new chemical entity. Early communication and consensus with FDA is a must pertaining to the integration of your Phase 1 data. A RTF - refusal to file will be issued by FDA, without question, if the pooling strategy is not agreed to prior to filing. Always communicate with FDA early on when determining the presentation of your Phase 1 integrated safety data and statistical pooling strategy for clinical/regulatory CTD submission.

Phase 1 Clinical Trial Trends - Staffing by Position

Overall, because a Phase 1 clinical trial typically requires such a small number of patients compared to Phase 2 and 3, fewer FTEs are required to manage clinical study conduct and performance. In my experience and because of smaller patient numbers, simple resource trends surface relating to how to staff by position, a Phase 1 clinical trial.

In the last years, and on average, pharma typically outsourced 41% of staffing by position related to Phase 1 clinical trial activities, SOPS and tasks in 2006. This number, in the first quarter of 2010, increased to 59%. Clinical staffing by position, whether it be FTEs or outsourced, typically trends and follows a distribution profile - In-house FTEs/Outsourced, unless otherwise specified:

• Clinical directors, VP - 100% FTEs
• Clinical trial managers - 100% FTEs
• Data management - 50%/50%
• Medical writing - 100% FTEs
• Biostatisticians/bioanalysis - 30%/70%
• Regulatory - 100% FTEs
• Clinical quality control - 100% FTEs
• Clinical quality assurance - 100% FTEs
• Clinical trials supplies - 100% FTEs
• CMC - 100% FTEs
• Contract management - 25%/75%
• Drug safety - 50%/50%
• Pharmacovigilance - 45%/55%.

A Phase 1 clinical trial can be simply and concisely budgeted with early planning development with respect to the clinical protocol and statistical analysis plan. Due to Phase 1 clinical trial simplicity in design, easily measured endpoints, most commonly, patient safety and tolerance, new chemical entity proof of concept design and small numbers of patients involved - the budget can be exact, the ROI easily achieved, results quickly analyzed. A Phase 1 clinical trial resource distribution profile, staffing by position, as seen above, demonstrates that pharma, at this clinical level of drug development maintains staffing by position in-house. Why? During the Phase 1 clinical trial period of drug development - this is the time for pharma take a go/no go decision with respect to the future development of the drug. The decision must come from pharma and only after careful consideration and review of Phase 1 clinical trial data. I strongly advise that go/no go decisions pertaining to Phase 1 clinical trial continuance or not, remain the responsibility and accountability of pharma. Guidance from FDA recommends the same good clinical practice. Plan early, resource and staff by position accurately and appropriately, follow good clinical practice, design concise clinical protocols and SAPs. The Phase 1 clinical trial is the least expensive trial (or should be) in the clinical drug development process and path to regulatory clinical submission.