Project Management in the Pharmaceutical Industry

We are grateful for the fine efforts of Bob Staples who has served as guest editor of the 1989 Special Topics Issue of the Project Management Journal and for this Showcase Project. We believe all will benefit by a deeper understanding of Project Management in the Pharmaceutical Industry as presented in this article. We also appreciate the contributions of these authors. The story of VASOTEC® is an outstanding contribution to the literature of project management. Thanks to Merck and Co. Inc., and all the individuals who contributed to creating this story and especially to the authors for preparing it for publication.

Robert Staples, 1989 Special Topics Editor

Introduction To The Showcase Project

Representing a significant pharmaceutical advance in the treatment of high blood pressure, VASOTEC® was discovered and developed on the campuses of Merck Sharp & Dohme Research Laboratories, a division of the most admired corporation in the United States. Its evolution may be judged a contemporary pharmaceutical project management success story on the basis of several important scientific, medical, and project management criteria.

First, in contrast to “tradition,” VAS-OTEC® was born of a “rational approach” to drug discovery—a process based upon de novo enzyme inhibitor design.

Second, the massive development effort that transformed the active new chemical entity into a FDA-approvable New Drug Application (NDA) was accomplished in just over four years, about 20-40% faster than the industry average, and project costs were within 10% of original projections. Then, three more related registration packages — a new formulation, an additional claim, and a new combination product—were submitted within nine months of the original NDA.

These achievements did not happen by chance. They were instead the result of a project management process conceived within the culture and executed within a framework based on good communications and highly-coordinated teamwork.

As measured both by manpower and the various specialty disciplines requiring coordination, the scope of this R&D project was enormous. Patient and thoughtful decision-making processes on the part of R&D, as well as corporate management were an integral part of the success.

Pharmaceutical Project Management: Some Background. To one degree or another, pharmaceutical R&D projects have always been managed by people at appropriately high organizational levels. The scope of such projects, however, has expanded greatly since the mid-1960s. Medical, legal, economic, regulatory, and even social and ethical issues must now be considered in much greater detail than ever before.

During the past quarter century, the requirement for huge amounts of timely data coupled with pressures to contain costs and control expensive resources demanded changes in management systems and sparked the evolution of project management hardware and software tools. The adaptation in the mid-1960s of some of these “new” project management philosophies, organizational forms, procedures and tools by some leading health-care companies marked the beginning of the current era of pharmaceutical R&D project management.

Since its first meeting in 1969, PMI has provided a forum for consideration of pharmaceutical project management issues. To be sure, pharmaceutical R&D people published fewer project management articles in PMI publications than did their engineer and construction colleagues, but many minds were at work in our industry creating or adapting concepts, tools, and techniques that made unique sense to pharmaceutical project leadership.

With just one out of every 10,000 newly discovered drug compounds ever warranting further development and but one in every five of the “developed” compounds culminating in a viable product, the pharmaceutical R&D process demands enormous resources and carries a formidable price tag (a company risks an average of $140 mil-lion per development compound). Though there are many recipes for success, Merck's development of VAS-OTEC® exemplifies a culture-sensitive, research-driven “style” of project management, as well as outstanding R&D. Other “styles” have worked well in other company cultures. SmithKline & French's development of Tagamet in the mid-1970s, for example, is representative of a more computer-aided management “style,” at least in terms of project planning, tracking, and reporting via network-based software.

Discussion of “styles” and applicability of “organization” and systems tools have received much attention in PMI, particularly since the conception of the Pharmaceutical Track in 1979. It was, in fact, the relevance of contemporary R&D project management in the industry that prompted the creation of a Project Management Subsection within the Pharmaceutical Manufacturers Association (PMA) in the mid-1980s. The proliferation of project management education and training opportunities in company-sponsored events along with specially-structured seminars and workshops at universities and private consulting firms attests to a continuing interest in designing and implementing responsive project management. Predictably, younger biotechnically-based companies are examining project management concepts which might hasten their discoveries to the marketplace.

Effective pharmaceutical project management enables new medical discoveries to reach us sooner and, perhaps, at less cost. To that extent, researchers and practitioners of project management art and science influence the treatment of disease and maintenance of health worldwide. Their process, therefore, deserves our close attention.

FROM THE LABORATORY TO THE PHARMACY:
Therapeutic Drug Development at Merck Sharp & Dohme Research Laboratories

Dr. John Engelhart, Director, Project Planning and Management, MSDRL

Dr. Martin Malkin, Executive Director, Planning and Management, MSDRL

Mr. Richard Rhodes, Director, Project Planning and Management, MSDRL

A Historical Perspective

In the early 1920s, Sir Alexander Fleming, working alone in his research laboratory, came upon an interesting biological phenomenon: An antibacterial ferment found in such substances as egg whites, tears, and various microbes was capable of dissolving living bacteria, especially the strain of bacteria known as cocci.

The therapeutic ramifications of this discovery were not fully apparent until six years later, when, through one of the serendipitous turns of science, Fleming observed that a plate culture of staphylococcus was actually destroyed by a mould whose active agent was penicillin. By applying the penicillin to infected surfaces and injecting it into animal subjects, Fleming confirmed what he had already suspected—penicillin was a non-toxic antiseptic agent that in many important ways was superior to other potent chemicals.

Not until World War II, under the auspices of another small group of British scientists, were all the pharmacological properties of penicillin sufficiently identified to facilitate the drug's large-scale manufacture and distribution. Nevertheless, the story of penicillin is illustrative of the pre-war pharmaceutical experience, in which a single individual or group of scientists could make significant therapeutic contributions. Large interdisciplinary teams and rigorous regulatory agency data requirements (prior to 1962, the United States Food and Drug Administration required only that a drug satisfy specified standards of strength, purity, and safety) were still a thing of the future.

Much had changed by the mid-1960s. Propelled by a confluence of forces—advances in medical technology and know-how, increasing governmental regulations, the occurence of catastrophic adverse experiences with a marketed drug previously considered to be very safe, larger drug development costs, and a far more competitive environment, among others—the drug research and development process evolved into an intricate web of activities, involving sometimes more than 15 separate research, development, marketing, manufacturing, and regulatory specialties, and dozens of individual players. The dawning of this new age of development forced pharmaceutical companies to address the need for the establishment of a systematic approach to the management of drug development. Without such an approach, pharmaceutical companies risked losing their perspective on, and control of, the overall process.

During the last 20 years, a number of different approaches to the management of drug development have been tested by the industry. Some pharmaceutical companies have addressed the problem with computerization, capitalizing on the technology's enormous memory and flexibility to track and manage intra—and interdepartmental relationships and activities.

ABOUT THE COVER

Several tools are used to study the chemical structure of possible leads. One of these tools is the computer which is being used to study the relationship between structure and activity. Shown on the cover is the molecular form of VASOTEC®, the drug development subject of this article. Shown at left is the classical chemical structure of VASOTEC®.

Merck & Co., Inc.:
The World's Largest
Ethical Pharmaceutical Company

Responsible for such early medical successes as the discovery and/or development of cortisone, vitamins B1, B6, B12, K1, and penicillin, Merck & Co., Inc. has grown into the world's largest ethical pharmaceutical company, with 1988 sales over $6.0 billion. Today some 150 Merck prescription products, including the cholesterol-lowering agent, Mevacor®, the recombinant hepatitis B vaccine Recombivax HB®, and the hypertension medication VASOTEC® are marketed throughout the world. Fourteen such products, representing nine different therapeutic areas, individually accounted for more than $100 million in 1988 sales. Merck can trace its beginnings to two apothecaries. The first, founded in 1668 by the German Merck family, had grown by the late-19th century from a small-scale producer of quality medicines to a major manufacturer of medicinal chemicals with sites in both Darmstadt, Germany and New York.

The second was started in 1845 in Baltimore, Maryland by Alpheus Phineas Sharp, a pharmacist who rolled his own pills, mixed his own salves, and bottled and labeled his own medicines. In the 1850s, Louis Dohme joined Sharp as partner, and after the Civil War, Sharp & Dohme expanded the enterprise to the manufacture of medicines for pharmacists across the nation.

MERCK & CO., INC.
ORGANIZATIONAL CHART (Early 1980s)

When VASOTEC® was being created in 1980, the shepherding of drugs through the development cycle fell to eight project coordinators reporting to the Director of Project Planning and Management. They coordinated a network of activities and interrelationships spanning not only all basic research and development groups of Merck Sharp & Dohme Research Laboratories, but the marketing and manufacturing representatives of Merck Sharp & Dohme Domestic and International divisions as well.

Merck & Co., Inc., and Sharp & Dohme, Inc., were merged in 1953. The company's research division, Merck Sharp & Dohme Research Laboratories, was actually launched two decades earlier, with the establishment of the Merck Institute for Therapeutic Research. One of the first pharmaceutical science laboratories in the United States, Merck's research division quickly gained an international reputation in the development of new products. Research became the company's guiding light.

Today, Merck's research and development investment exceeds a half-billion dollars annually, and its worldwide network of 16 pharmaceutical research facilities spans six countries. Of Merck's 31,000 total employees, approximately 3,600 are engaged in the discovery and development of medicines for human and animal health products. More than 50 scientific disciplines—including organic chemistry, biochemistry, analytical chemistry, biochemistry, molecular biology, biophysics, genetic engineering, virology, pharmacology, microbiology, immunology, bacteriology, cell biology, toxicology, pathology, biochemical and chemical engineering, and human and veterinary medicine—are represented in the laboratories.

Merck's contributions to the field of pharmaceutical science touch on nearly every aspect of human and animal health. Merck's success in vaccine development dates from 1898 with the first commercial production of the smallpox vaccine in the United States, and includes as well the first influenza vaccine, the first live, attenuated measles, mumps and rubella vaccines, and the world's first genetically-engineered hepatitis B vaccine. Merck has also been a major player in the area of cardiovascular therapy, developing a series of drugs targeted to the treatment of hypertension, congestive heart failure, cardiac arrhythmias, and high cholesterol. Likewise, with such therapies as Pepcid® for the control of gastric ulcers, Merck has made significant advances in the field of gastrointestinal disease. A series of animal health products, primarily for the control of parasites, have also emerged from the Merck Sharp & Dohme Research Laboratories.

The research continues at the Merck Sharp & Dohme Research Laboratories; the cardiovascular program continues as scientists look for new therapies to treat heart disease.

Finally, Merck has made considerable headway in the development of drugs for rare diseases and afflictions. Most recently, Merck donated Mectizan®, an agent shown to be effective in helping to prevent the human parasitic disease Onchocercia-sis, to areas whose populations are afflicted with river blindness. The company continues to provide support for this humanitarian effort through an independent Review Committee of leading international health authorities which oversees the drug's distribution.

Held in high regard by both the pharmaceutical industry and the general business community, Merck has been the recipient of such honors as Fortune magazine's Most Admired United States Corporation for the last three years, Forbes magazine's Most Innovative Company in the Pharmaceutical Industry, Business Month magazine's Best Managed Company, and Business Week magazine's Best in Public Service.

Merck & Co. Inc., however, approached the issue by introducing a new staff function—the project coordinator—as a means of strengthening communications and monitoring the activities of the overall program. At first, Merck project coordinators served primarily as facilitators—individuals who relied on their communication and organizational skills to ensure that all the participants in the drug development process were informed as to the objectives and timetables of the program.

In the late 1970s, more emphasis began to be placed on the project team as a focal point for development programs. At the same time, the computer began to take on a significant role in assisting the project coordinator and the project team in tracking program activities. Importantly, this technology, was and continues to be, viewed as a supportive tool, and not the prime focus of management activity.

Merck's new emphasis on a more comprehensive approach to project management coincided with the development program for VASOTEC®, a major advance for the treatment of hypertension. With support from the new project management process, Merck was able to meet, and at times surpass, its project goals. VASOTEC® proceeded through development within just four years—an unusually rapid rate by pharmaceutical standards—and gained FDA approval within 27 months of filing a New Drug Application. Further, just two years after the product's launch, VASOTEC® became the number one antihypertensive drug in the United States and is today one of the leading pharmaceutical products in the world.

Approaches to Drug Discovery

Each of the 2,400 drugs now sold in the United States has traveled a unique journey from its first discovery in the research laboratories to its appearance on pharmacy shelves. Historically, very little was known about how drugs actually worked; more recently, the mechanism of action of some drugs has been unraveled at the molecular level, and many therapies targeted to a precise mechanism are currently sought.

There are three basic approaches to drug discovery. The first is empirical research, in which scientists randomly screen thousands of chemical compounds until a few promising agents are uncovered. The second method of discovery depends on the fermenta-tion of organisms found in soils or plants and relies as well on the empirical screening of the compounds generated. The third way is by design.

Merck Sharp & Dohme Research Laboratory building in West Point, PA.

In the 1970s, Merck was a pioneer in this third approach to drug discovery. Led by the president of the laboratory division, Dr. P. Roy Vagelos (now Merck's Chief Executive Officer), Merck scientists began to design new drug compounds proactively based on their knowledge of the specific biochemical reactions responsible for the target disease. This “rational” approach involves probing the biochemistry of various diseases, pinpointing the structures and mechanisms responsible for the physiological response, and, finally, designing compounds that might counteract the disease process at the molecular level. As its name connotes, the rational method leaves far less in the hands of either serendipity or nature.

VASOTEC®:
Searching for a Solution

The story of VASOTEC® actually begins in the early 19th century with the pathophysiologic studies of Dr. Richard Bright. By studying the appearance of the kidney in various disease states, Dr. Bright was able to uncover the association between kidney damage and cardiovascular failure and, thereby, set into motion a long series of investigations relating to the interplay between the kidney and the rise of blood pressure.

By the 1940s, scientists had amassed enough evidence to support the theory that renin, a protein formed in the kidney, had the ability to act on a substrate in the blood plasma; that substrate, when altered, had a tendency to constrict the blood vessel walls, and thereby raise blood pressure.

As we understand it now, the process goes something like this. A fall in blood pressure causes a diminution of renal blood flow which triggers a release of renin from the kidney. Renin acts on a plasma protein, angiotensinogen, to form the inactive compound angiotensin I. Angiotensin-converting enzyme (ACE) then converts angiotensin I into angiotensin II. Angiotensin II, a polypeptide, is a potent vasoconstrictor, and stimulates the secretion of aldosterone. Aldosterone increases the reabsorption of water and sodium in the kidney, and it is this phenomenon, together with the constriction of the blood vessel walls, that ultimately elevates the body's blood pressure.

Over the years, scientists have paid scrupulous attention to each link in this chain of events. Recognizing that angiotensin II plays a key role in the elevation of blood pressure, several approaches were undertaken to prevent this polypeptide's formation or action. In the mid to late 1970s, the most productive approach lay in deciphering the nature of the angiotensin-converting enzyme and the structure of its active site.

Nature lends a hand. The venom of a Brazilian pit viper played a pivotal role in the discovery process. The viper's bite produces, among other effects, a drop in blood pressure, and researchers noted that components of the venom could potentiate a vas-odilating hormone, called bradykinin. Later, these same components were shown to inhibit ACE and ultimately a series of small peptide inhibitors were isolated, including one known as teprotide.

Though efficacious in hypertensive patients with either normal or high renin levels, this peptide was not orally active and had to be administered by injection. Continuing this line of research, scientists at Squibb were subsequently able to design a potent, low-molecular weight inhibitor of ACE, designated captopril, that was orally active.

Merck Sharp & Dohme Research Laboratories begins the search. A long history of cardiovascular research and antihypertensive drug development made Merck Sharp & Dohme Research Laboratories (MSDRL) a natural candidate for the further refinement of the ACE inhibitor concept. As early as 1974, MSDRL had begun the process of screening compounds—drawn from an existing compound collection, as well as fermentation broths—with the hope of discovering an effective ACE inhibitor. The research process was intensified one year later with the establishment of an Enzyme Inhibitor Design project, and the shift to a far more rational approach which depended on the design, rather than the serendipitous discovery, of the inhibitor compound.

In 1978, a team of seven chemists achieved the hoped-for break-through—the design of a compound that demonstrated interesting levels of activity. Merck's attention now turned to creating a safe and effective entity suitable for marketing.

“We had two very specific goals,” recalls Dr. Arthur Patchett, Vice President of the New Lead Discovery Department. “The first was to produce a drug with a favorable safety profile. The second was to create a long-acting compound that would only have to be taken once a day. An ACE inhibitor with these characteristics would, we believed, offer hypertensive patients a very real alternative to existing drug therapies.”

Because the success of any drug ultimately depends on its relatively early appearance in the competitive marketplace, Merck was in a race against time. Convinced that Merck was now on the brink of a significant contribution to antihypertensive drug therapy, Dr. Patchett took immediate steps to enlarge the synthetic chemistry group and file the necessary patents.

Dr. Patchett reflects: “In research, success depends on the ability to recognize where breakthroughs may be made. It also depends on the ability to mobilize the resources essential to making the breakthrough. Thankfully, Merck has outstanding scientists in leadership positions who are willing to move quickly to capitalize on promising new developments as they occur in basic research.”

Once a compound has been discovered, its development into a viable drug therapy can take anywhere between five to ten years and involve as many as 15 different scientific disciplines. A series of time-saving measures taken throughout the development of VASOTEC® enabled Merck to file a total of four New Drug Applications within just six years of the time the drug was approved for development.

The Merck ACE inhibitor team, which grew from several scientists to over forty chemists, biochemists, and pharmacologists between the years of 1976 and 1980, studied more than 200 variants of their lead compound. Each of these had to be assayed for enzyme inhibitory potency, and the active ones were then evaluated in animals to determine which ones had the best efficacy and duration of action. Interdepartmental collaborations proceeded informally allowing the designers to adjust their plans as quickly as possible to the latest testing results.

By the summer of 1979, Merck chemists and pharmacologists had developed a series of ACE inhibitor candidates that satisfied the target goals. These were then formally presented to the MSDRL senior research management committee, who reviewed, among other items, how the candidates compared with competitor compounds; data relating to absorption, specificity, and duration of action, and metabolism. Three candidate compounds—one of which was enalapril (trade name, VASOTEC®) were approved as safety assessment candidates, and subsequently moved beyond the scope of basic research.

From Research to Development: Making the Transition

Merck is a research-driven company: Decisions regarding which disease targets and drug candidates receive corporate funding and support are based largely on the insights of those who are most familiar with the advances being made in the basic medical sciences, and not initially on specific marketing needs. Formal project management begins when a promising new drug candidate is ready to be moved out of basic research and into the development phase.

The initial task of the new development team is to prepare what will be the first in a long line of summary documents. Called the New Product Proposal, this summary document achieves the following:

• reports on the biological activity of the candidate and the clinical implications of its pharmacological or biological profile;
• comments on the candidate's potential as a drug therapy (that is, whether or not it will be viewed as a significant breakthrough or a useful advance) as well as the competitive environment currently and at the expected time of approval;
• specifies the chemical form of the candidate;
• summarizes patent coverage in the United States and worldwide; and
• outlines proposed project goals.

On the basis of the team's recommendations, management will either open the door to the candidate's further development, or send it back to research.

Merck Project Planning and Management: Key Accountabilities

Once a candidate receives the official nod of approval, Project Planning and Management begins to coordinate those activities essential to the start-up of the development process. Such activities include:

• forming the project team;
• defining key issues, agendas, and individual assignments;
• providing upper management with routine reports on the status of the compound;
• initiating the production of bulk drug for subacute animal toxicology studies, formulation development, and initial clinical supplies;
• ensuring the appropriate definition of oral and intravenous dose forms;
• determining the assay methods for detection of the drug and metabolites in body fluids; and
• launching animal toxicology studies that will support multiple-dose clinical studies.

With these basic building blocks in place, Project Planning and Management begins to shepherd the drug through the various stages of development—essentially the seven phase process described below:

• Preclinical Phase. In this phase, the compound must be produced in quantities sufficient for further development studies; the chemical manufacturing processes improved; the appropriate initial formulations of the compound developed; analytical methods for evaluating the stability and purity of the drug substance established; assay methods to measure the compound in the body defined; and the safety of the drug in animals explored. How the drug is absorbed, metabolized, distributed in tissues, and excreted by animals is also studied at this time, as a predictor of the drug's activity and properties in man.
• Investigational New Drug (IND) filing. In the IND filing, the project team summarizes all animal safety, animal pharmacology, dosage form information and process chemistry findings for the review of the Food and Drug Administration (FDA). The clinical protocol for the first Phase I study is also sent to the FDA for review. If these data are sufficient to satisfy the FDA, and safety in human subjects can be anticipated based on an acceptable safety profile in animal studies, clinical development is allowed to proceed.
• Phase I. The safety of the candidate drug is evaluated in healthy volunteers (about 6-12 per study), first as a single dose and then as multiple doses in several studies. These are usually conducted in a clinical hospital setting where the subjects can be monitored 24 hours a day. The Phase I studies are conducted to demonstrate preliminary safety in man before administration of a drug to patients with a specific disease.
• Phase II. The efficacy of the candidate drug in treating the disease or condition in question is assessed through a series of closely monitored clinical studies in patients afflicted with the disease. A range of doses is evaluated to define the optimal dose for use in the Phase III studies.
• Phase III. The candidate drug is tested in a large number of patients to confirm both usefulness and safety, in the setting in which fu-ture patients are most likely to receive it (i.e., the patient receives the drug from the doctor, takes the tablets or capsules as prescribed at home, and then returns to the doctor for periodic check-ups).

  These studies are designed to compare the active investigational drug with a placebo or with another drug that gives the same therapeutic effect. Such Phase III trials are blinded, i.e., neither the patient nor the investigator and Merck medical staff are aware of which drug or placebo has been given to each patient.

  Testing safety, efficacy, and dosage levels in thousands of patients around the world provides the drug development team with a more accurate picture of the drug's potential benefits and drawbacks. By the end of Phase III, the drug sponsor will have accumulated enough information to be able to recommend a specific formulation of the compound for a specific patient population, at very specific dosage levels.

• New Drug Application (NDA) filing. In order to market the new drug candidate, pharmaceutical companies must seek approval from each country's regulatory agency. This request for approval takes the form of a massive document that contains all preclinical and clinical results. In the United States, FDA approval of an NDA currently averages 32.4 months.
• Post-NDA filing activities. With the filing of the NDA, attention must now turn to such areas as product claims support (to supplement the core registration package with additional indications and/or dosage forms), product pricing support (to ensure the new product will be an economic success), medical marketing support (to ensure all product sales persons receive adequate training in the compound's attributes and profile and that all promotional materials are accurate), and manufacturing support (to ensure that manufacturing and quality control representatives have sufficient information to fulfill their responsibilities).

Dr. Martin Malkin, right, Executive Director, Planning and Management, and Dr. Arthur Patchett, left, Vice President of the New Drug Discovery Department, review one of the basic tools of drug discovery—a molecular model of the compound VASOTEC®. A member of MSDRL's project planning and management group since 1974, Dr. Malkin currently oversees a staff of 50 individuals of which 14 coordinate all projects in development.

To address the diversity of needs and issues that will inevitably arise over the course of this phased, five-to-seven year development cycle, Project Planning and Management must focus on four primary activity areas: team composition, communications coordination, program tracking, and regulatory support.

Team Composition. Charged with the responsibility of coordinating all of the activities required for the realization of a new drug therapy, Project Planning and Management's first priority is to help facilitate the early assignment of team players and accountabilities. As currently practiced, Merck project teams are composed of the participants in the clinical program (clinicians, medical program coordinators, statisticians, and data coordinators); the scientists responsible for drug formulation, drug metabolism, assay development, process research, and toxicology; and regulatory affairs and marketing representatives.

As is now the case with all Merck project teams, the team leader for the development of VASOTEC® was selected by the vice president of Clinical Research. A cardiovascular clinical research physician with specific knowledge of antihypertensive drugs, this individual was assigned line responsibility for the entire clinical program and shared general coordination responsibilities for the activities of all additional team players. (The individuals participating in the project team for VASOTEC® numbered some 50 individuals by the filing of the NDA.) Responsibility for designing the various clinical protocols, securing expert outside physicians to conduct the clinical studies, monitoring the clinical studies, interpreting clinical trial results, and guiding the preparation of the NDA also fell to the team leader and his staff of cardiovascular physicians.

More than a solid grounding in the science of cardiovascular disease is required to successfully spearhead the drug development process. Indeed, perhaps the most critical qualification for a team leader in the pharmaceutical industry is a strong sense of interpersonal, leadership, and communication skills—an ability, in short, to effectively arbitrate the sometimes competing interests of several different departments. Also key are a strong understanding of the drug development and regulatory process, a thorough knowledge of the corporate culture, a systematic approach to getting things done, experience in conducting clinical trials, and, finally, an ability to achieve that delicate balance between complying with key schedule constraints and minimizing unnecessary burdens on individual team players.

Co-coordinating the massive planning and decision-making effort associated with VASOTEC® was one key project coordinator, Dr. John Engelhart, whose responsibilities cut across all disciplines, and a second project coordinator, Mr. Richard Rhodes, who held primary responsibility for coordinating both the filing of the NDAs and the Japanese development program.

Each of these reported to the then-Director of Project Planning and Management, Dr. Martin Malkin.

The project coordinators for VAS-OTEC® were drawn from a field of eight Merck project coordinators, whose total accountabilities can include 200 different drug development programs, and who are usually given their assignments on the basis of therapeutic areas. This multi-project planning environment endows Merck's coordinators with a broad overview of development activities and enhances their ability to integrate key processes and identify appropriate priorities.

To manage this vast network of interrelationships and goals, the project coordinators must possess a unique hybrid of knowledge, experience, and planning and communication skills. In addition to many of the prerequisites described for an effective project leader—an ability to navigate the corporate environment, skill in putting forth and upholding coherent project plans, adeptness at identifying and resolving potential resource conflicts—project coordinators must also offer a highly organized and systematic approach to the overall development process, and be sufficiently familiar with the tools and technologies of project management. Because project coordinators typically have more access to upper-level management, they must additionally be adept at analyzing and disseminating key strategic documents. Perhaps most importantly, project coordinators must be good at anticipating, identifying and obtaining satisfactory resolutions to issues and problems. Put another way, pharmaceutical project coordinators must have the uncanny ability to separate the wheat from the chaff, while still making use of the chaff.

The dynamic nature of the drug development process clearly does not lend itself to standardized retrospective monitoring of target dates, budget, manpower needs, or drug supplies. Merck, therefore, guides its development activities according to the vision of a master plan, orienting its activities around key target dates. Organized as a staff function, project coordinators are free to acquire a broad perspective on the overall process and to take the kinds of actions necessary to shepherding projects through the extremely complex development cycle.

Of equal significance, the project coordinator position is inherently neutral, and thus more likely to gain the trust and cooperation of a diversity of interlocking, potentially competitive groups. This neutrality is especially important in a company as complex as Merck: MSDRL includes more than 3,600 employees and 50 scientific disciplines; MSDRL's worldwide network of 16 pharmaceutical research facilities spans six countries; and MSDRL is characterized by both strong vertical intradepartmental reporting relationships and effective horizontal coordination and planning roles. In addition to paying close attention to the activities of the research organization, Project Planning and Management must also interact with all areas of Merck's 31,000-person organization; the concerns of Merck's domestic and international marketing groups, for example, must be considered and represented throughout MSDRL's Clinical Operating Plans.

Communications Coordination.

Communications are the lifeblood of the drug development process. The immediate exchange of unambiguous data enables each group to proceed without hesitation towards the same basic goal: the time-effective filing of a comprehensive NDA. In addition to a heavy reliance on informal communications and information sharing, project coordinators made use of a series of meeting forums to ensure that all issues were raised and resolved within a reasonable time frame.

Four primary vehicles—the Development Coordinating Committee meetings, In-depth Review meetings, Project Team meetings, and Clinical Research Committee—and three secondary (those convened to address specific issues) vehicles—Interdisciplinary Drug Development committee meetings, Bioavailability Team meetings, and Medical Marketing Interface Meetings—enabled the team to meet its targets:

• Development Coordinating Committee meetings, comprising the president of MSDRL, his vice presidents, and selected research management (including the head of Project Planning and Management) convened once a month to review the status of every single compound in the development phase. Empowered by a centralized line organization, the members of this committee exert a strong influence on the direction of each drug development program by setting priorities and assigning key resources.
• In-depth Review meetings, composed of research management vice presidents, marketing management, and key project team members convened twice a year to discuss the status of a single candidate (in this case, VASOTEC®). These meetings are chaired by the president of MSDRL following an agenda and subsequent minutes prepared by the project coordinator.
• Project Team meetings, comprising all team members, and convened every four to six weeks to review program status. In the case of VASOTEC®, the project coordinators had responsibility for the agenda and minutes of these particular meetings.
• Clinical Research Committee meetings, comprising members of Clinical Research, Regulatory Affairs, and Project Planning and Management convened every month to provide a forum for approving all Clinical Operating Plans and to en-sure that Marketing's viewpoints and needs are integrated into the Clinical Operating Plans.
• Interdisciplinary Drug Development Committee meetings, comprising representatives from the preclinical and clinical departments convened every month to discuss key interdisciplinary issues related to drug metabolism, pharmacology, safety assessment, and/or clinical research for selected programs.
• Bioavailability Team meetings, chaired by the head of Drug Metabolism convened every month to address issues relating to the pharmaceutical (i.e., dosage forms and dose strengths) and drug metabolism properties of the drug candidate.
• Medical Marketing Interface meetings, comprising representatives from the research and marketing divisions convened on an as-needed basis to discuss issues re-lating to business and research program needs, as well as concerns left unresolved at the project team level.

Dr. John Engelhart, left, Director, Project Planning and Management, and Dr. Victor Grenda, right, Senior Director of Process Research, consider alternate process chemistries of VASOTEC® that will facilitate the time and cost-effective production of bulk drug quantities sufficient to meet various preclinical and clinical study requirements. Himself the author of 27 U.S. patents, Dr. Engelhart brought a thorough understanding of pharmaceutical science to his role as prime coordinator of the project for the development of VASOTEC®.

In addition to these and other meetings, the project coordinators updated research management on crucial findings, issues, or activities through two basic documents: the Monthly Highlights Report, which summarized key development activities, and the Critical Activities Status document, a compendium of upcoming activities and related target dates which was reviewed at each monthly Development Coordinating Committee Meeting.

Program Tracking. Because drug development can take from between five to ten years and is by nature unpredictable, the process does not readily lend itself to detailed schedule controls. Thus, while thousands of activities are entailed, Merck project coordinators narrow their tracking focus to those 50 to 100 activities that are most pivotal, and far less subject to change.

Individual and team schedules were built around key target dates. The most critical target date, of course, was that of the NDA filing, officially designated as mid-1984. By early 1981, however, anticipated competitor pressures prompted the Development Coordinating Committee to bring the NDA filing date closer to late 1983. Already operating within a tightly compressed schedule, the project coordinators and team were now presented with a new challenge: the need to cut six months from the development timeline. Through a series of negotiations with the departments responsible for the clinical database, the timetable for the completion of the Phase III studies and compiling the NDA was compressed by the necessary six-month period.

Subsequently, it was determined that three months could be cut from the carcinogenicity studies' report preparation by compressing the timetable for histology and lab analyses and condensing the report writing time. This prompted further negotiations to condense the clinical programs by another three months—a goal which was ultimately met.

Two primary project management tools facilitated the tracking of the development of VASOTEC®. The first was the NDA schedule, which detailed the critical activities (up to 1,000) during the clinical data gathering and analysis process leading to the filing of the initial single entity tablet NDA in September of 1983. Three more registration packages were filed in the next nine months for a new formulation, a combination product, and a new claim for congestive heart failure (CHF).

The second was ARTEMIS®. Though Merck did not fully tap the potential of this computerized project management program until after the development of VASOTEC®, the project coordinators did begin to exploit its fundamental utility as a project tracking system over the course of the program.

Regulatory Support. As previously stated, the ultimate goal of the project team is to file a successful NDA with the FDA and its counterparts across the globe. These applications are not, of course, the first time that the drug candidate appears on the regulatory agency desks. Updates on company activities are received in the form of Investigational New Drug Exemption filings, adverse experience reports, pre-New Drug Application conferences, annual IND progress reports, and a host of informal communications all along the way.

Most pharmaceutical companies today take a global approach to the development of new drugs. Registration strategies must reflect the unique character of the regulatory process in each country. Many countries, for example, require not only approval from the health authorities, but also approval on product pricing and/or reimbursement. In addition, some countries prefer one or more pivotal studies to be conducted on site using local experts who provide credibility and support for the registration dossier. Further, each country's regulatory agency retains the right to negotiate the wording that appears on the product package insert, which serves as the official summary of the approved indications, routes of administration, dosage forms, warnings, and contraindications.

In the department of Regulatory Affairs, Merck has an established core of regulatory experts, whose role is to keep the project team abreast of key issues and to define regulatory filing requirements. This information is provided directly to the medical team, marketing division, and the project coordinator to ensure that critical regulatory guidelines are broadly communicated.

To achieve simultaneous international filing, Merck creates a core registration package summarizing all major preclinical and clinical study findings and makes this available throughout the world. Any special, country-specific data requirements are added on an as-needed basis.

The one exception to the rule is Japan, which, by reason of its regulatory policies, requires the definitive clinical studies to be conducted with Japanese subjects. (Japan also requires certain preclinical data to be developed within its borders.) Merck relies on its Japanese subsidiary, Banyu Co. Ltd., to carry out the local development of the compound in a manner that satisfies both Merck and Japanese requirements. In the case of VASOTEC®, Merck assigned U.S.-based project coordinator Richard Rhodes the responsibility of coordinating all Japanese development activities by maintaining contacts with both the Banyu and Merck Sharp & Dohme Research Laboratories project teams.

VASOTEC®: The Journey
Through the Development Cycle

Setting the wheels in motion. Research scientists require only milligrams to grams of compound to conduct their activities in the drug discovery phase. In the development cycle, the quantity must be increased to kilogram levels to facilitate the various preclinical and clinical studies that will be undertaken over the next several years.

The next order of business, therefore, is the safe and expedient preparation of the compound so that each department may be assured adequate supplies. At Merck, these activities take place within the area of Process Research and Development.

“Time is of the essence,” says Dr. Victor J. Grenda, Senior Director of Process Research. “The toxicology and pharmaceutical departments cannot do their jobs until we have done ours. By the same token, we have a responsibility to ensure that the compound we supply for their evaluation will have precisely the same properties as that manufactured on a much grander scale several years down the road. This can be a time-consuming process.”

Often, as with VASOTEC®, the chemists within Process Research begin building a supply of compound by the chemistry initially utilized for preliminary toxicology and pharmacology studies. At the same time, more formidable synthetic schemes—those more attractive for eventual manufacture—are explored.

“The original synthesis of VASOTEC®, which was based on traditional peptide chemistry, would have required an extensive manufacturing process,” says Dr. Grenda. “To meet our development agenda, we established a conceptually simple process that cut the number of processing steps in half.”

After its process chemistry is defined, the drug is made in bulk in one of Merck's pilot plants. Usually, several different investigational drugs are being moved through the pilot plant during the same time period. Merck accommodates this demand by using a modular facility, in which equipment and processing strategy has been designed to maintain flexibility to handle a number of programs in sequence.

Determining how much of the drug is needed by which department within what time frame is the responsibility of the project coordinator. Says Dr. Grenda: “Before the institution of formal project management at Merck, Process Research was in the position of responding to all bulk drug requests, fulfilling unanticipated demands, and balancing competing priorities. Often, we found ourselves needing to produce additional quantities of a drug long after we had moved on to other activities.”

Each department's specific drug quantity requirements are now channeled through the project coordinators. Though unanticipated requests still arise, the centralization of this information has greatly enhanced Merck's ability to respond to the critical bulk drug requests of the multitude of compounds under development.

Just as the drug must be scaled up from test tube quantities to kilogram quantities to satisfy preclinical and clinical study demands, plans must now be made to manufacture the drug for large-scale, commercial requirements. To satisfy this need, Chemical Engineering works closely with Merck's Chemical Manufacturing Division to design manufacturing facilities and equipment that can produce the bulk drug to the requisite Merck specifications—and meet quality standards. The chemical manufacturing plant process is usually demonstrated in concert with submission of a NDA, affording ample time to cross-check the manufacturing process and begin building drug inventories.

Assessing the compound's safety. Prior to administering a new drug to man, the possible toxicity of the compound must be explored in laboratory animals. Undertaken by the toxicologists within Merck's Safety Assessment department, these studies provide the clinicians with a presumably “safe” dosage level with which to begin evaluation in man. Additional preclinical studies assess the drug's effect on fertility and reproduction, its genetic toxicity (including effects on DNA and mutagenic potential), its carcinogenic potential, and its mechanism(s) of toxic change at high dosage levels. The latter enables the clinicians to gain a better understanding of the relevance that these toxic changes may have when the drug is administered to man at therapeutic dosage levels.

Though the FDA's Good Laboratory Practice Guidelines require that one person be responsible for each preclinical safety assessment study, Merck, recognizing the great complexity and interdependency of the studies, assigns responsibility for the development of all of a compound's preclinical safety studies to a single study director. Drawn from the Safety Assessment department, this individual represents the group in the project team meetings and serves as the project coordinator's key departmental contact throughout the compound's development.

Mr. Richard Rhodes, left, Director, Project Planning and Management, and Dr. John Irvin, right, Executive Director of Cardiovascular Clinical Research, with the 333-volume New Drug Application filing.^* The coordination of the massive NDA filing, three subsequent NDA filings, and the Japanese development program fell to Mr. Rhodes throughout the program for VASOTEC®.

As noted earlier, anticipated competitor pressures resulted in an accelerated program for the development of VASOTEC®, forcing Safety Assessment to conduct an unprecedented number of studies within an abbreviated period of time. In order to avoid delaying the development of other significant therapeutic agents then under study, Safety Assessment initiated the early studies of VASOTEC® in a contract laboratory; Merck's high study and report standards were ensured through frequent laboratory visits by both the study director and members of Merck's Quality Assurance Group. The timely completion of the toxicity studies was further facilitated through continuous communications with the project coordinator and an uninterrupted supply of the bulk drug to Safety Assessment laboratories.

Drug metabolism studies. After acceptable levels of safety were found for the compound, the project team initiated a series of animal drug metabolism studies in which the time relationships between absorption, distribution, metabolism, and excretion were determined. These data were needed to ensure that the toxicology models developed for establishing the drug's safety in man would indeed meet safety standards.

Also, the team used drug metabolism studies to answer key questions regarding the compound's desirable doses and routes of administration. By ranging the animal doses from a no-effect dose to a therapeutic dose to a maximum-tolerated dose, the team gained a clearer picture of what could be expected in human studies.

Designing and implementing the clinical research plan. Clinical research—the study of a drug in man—is the most time-consuming aspect of the entire development cycle. This phase can begin shortly after demonstrations of adequate safety in animals have been achieved, and the initial information regarding the absorption, metabolism, distribution, and excretion patterns of the compound has been gathered.

As a member of the clinical team for VASOTEC®, Dr. John Irvin, who is currently Executive Director of Cardiovascular Clinical Research, participated in the various clinical studies. Over the development cycle, he joined Richard Davies, MD, PhD, and Findlay Walker, MD, in the development of a master strategy for the clinical operating plan, the design of individual study protocols, the monitoring of studies to ensure compliance with time and quality standards, the evaluation of adverse experiences, the compiling of the results of individual studies, and the presentation of the clinical safety and efficacy of VASOTEC® in the form of the NDA.

As with every new drug candidate, the evaluations of this compound's effect in man took place in outside clinics, selected on the basis of the potential patient population, as well as the expertise of the monitoring physician. The patients in these trials were treated at no expense, while the physician and institution were reimbursed through a special clinical study grant.

Recalls Dr. Irvin, “The clinical pharmacology studies were tailored to help us answer some very specific questions about the mechanism and efficacy of the ACE inhibitor. Because we did not have a lot of information pertaining to the drug's impact on humans, we sought the greatest variety of patients possible—individuals with high salt levels and low salt levels, for example, or individuals with varied renal function.

“We were also interested in the synergistic impact of VASOTEC®, that is, the efficacy of the drug when used in combination with diuretic therapy. We additionally asked ourselves such questions as: Was the drug altered when administered simultaneously with calcium channel blockers, beta blockers, or anticoagulants? How did different dosages affect patients? Could intravenous administration of the drug affect or improve its onset factor?”

Many kinds of clinical trials were knit into the overall fabric of the program, including:

• parallel study designs (in which one drug in one patient group is tested against another drug, either placebo or comparative therapy, in another patient group);
• cross-over study designs (in which each patient is evaluated with two or more drugs or different dosage conditions);
• fixed-dose study designs; and
• titration study designs (in which increasing quantities of the drug are administered until an optimum lowering of blood pressure is realized).

In addition, Merck worked with a team of consulting academicians who, expert in the field of hypertension, helped assure that the design of the clinical trials was in fact as air tight as possible.

To conduct the Phase I clinical trials, the clinical team flew to Lausanne, Switzerland, where, under the auspices of Dr. H.R. Brunner, 21 healthy male subjects were administered the drug in a fully-monitored environment. According to Dr. Irvin, the study was conducted in two stages; the first of which determined the dose which completely inhibited the effect of the angiotensin; the second of which determined the dosage levels at which the compound became active.

“Our work in Switzerland provided assurance that VASOTEC® was sufficiently safe in man to allow us to proceed further with our experiments. We were also able to use the Phase I trial to determine the least amount of drug necessary to catalyze a modest decline in blood pressure in healthy volunteers.”

In the next phase of clinical trials, the team targeted a series of studies in patients with hypertension. In the initial Phase II studies, the same protocol was followed at three different sites: Boston, Philadelphia, and Montreal. Following a two-week, no-drug washout period, these inpatients first received single-rising doses of VASOTEC®, alternated with a placebo. Later, the patients were exposed to rising doses over a 30-day period.

Phase III of the trials was initiated as soon as the team had compiled enough evidence regarding the drug's efficacy and safety. Encompassing some 20 different sites of between 20 and 25 patients each, these multi-centered trials were conducted over a four to six month period and scrupulously monitored by trained Merck physicians. They enabled the team to confirm appropriate dosage levels.

By the time all the clinical trials were completed in March of 1983, over 40 Phase I and II clinical pharmacology studies and eight Phase III multi-center hypertension trials had been conducted to determine the safety and efficacy of VASOTEC®. In all, over 3,000 hypertensive individuals received the drug during the development phase.

“In retrospect, it appears as if we might have been overzealous in our design of the clinical trials, that we did in fact collect far more data than was really necessary to support the NDA,” comments Dr. Irvin. “Though one can never be too certain of a drug's safety or efficacy, experience has shown that a comfort level can be attained after some 2,000 patients (100 of which are severely afflicted with the condition) have been evaluated with the drug. If we did try to answer too many questions or respond to too many specifics, we nevertheless went a very long way towards building a better understanding of the mechanism of ACE inhibition.”

Did the presence of the project coordinators ease the burden of this tremendously complex process? “The project coordinators certainly made our job much easier,” says Dr. Irvin. “We put a lot of faith in their ability to identify and resolve issues before they could blossom into crises, to serve as liaison between the clinical scientists and senior management, and to establish meaningful agendas for our group meetings. We also relied heavily on their ability to usher the NDA package through its various steps of development.”

The Project Team
Meets its Target Goals

In September of 1983, a little over four years after enalapril emerged from the research laboratories as a promising new candidate, the project team submitted a 333-volume NDA for FDA approval. It was the largest such program ever undertaken in the division's history. Significantly, program costs through the date of this filing were within 10-percent of the original projections.

Within the next nine months, the team reached yet another difficult milestone: the filing of three additional registration packages—one for an intravenous formulation to be used in hypertensive patients who could not ingest an oral dose, one for a combination enalapril/hydrochlorothiazide drug for use in more severe cases of hypertension, and one for a new indication, that of congestive heart failure. At the same time, the project coordinators and clinical team participated in the pursuit of new indications and claims and coordinated a variety of marketing research activities associated with the launch of the new product. This post-NDA work on VASOTEC® continues today.

Lessons learned. The development program for VASOTEC® was conducted during a time of rapidly changing attitudes, both within and outside of Merck. The early 1980s saw, for example, a heightened presence of regulatory agencies in the drug review process, as well as in the establishment of stronger data guidelines for new drug development. It also saw the need for expanded agency contacts to ensure that the clinical program would satisfy regulatory requirements.

The 1980s also saw the beginning of the “megastudy” era, in which regulatory agencies began to require much larger databases to define a drug candidate's safety and efficacy. At the same time, pharmaceutical companies began to pursue claims that necessitated much larger studies to prove efficacy.

Merck was able to respond to these external circumstances by focusing greater attention on the coordination of divisional viewpoints with those of the regulatory agencies. This led to a more precise planning of clinical studies and an early definition of intended claims.

At the same time, the role of Marketing in the drug development process assumed greater importance than in previous years. Formerly a spectator in the early clinical study phases, Marketing was integrated into the team process far earlier by helping to define data needs for product promotion, and by identifying the potential of new claims and formulations. Finally, in terms of Project Planning and Management's role, the increased complexity of the clinical program shifted the emphasis from reactive coordination to a proactive role in assisting in program management.

Merck's drug development process has been greatly strengthened by its experience with VASOTEC®. Among the many lessons learned are the following:

• The assembly of a multidisciplinary project team at the time a compound is chosen for development is crucial to the drug development process. This allows communication channels to be opened as soon as conceivably possible and diminishes the opportunities for unchecked problems or issues.
• In order to handle the difficult medical issues as well as the increasing complexities of the development process, the clinician's role as team leader is greatly augmented by the support of an experienced project management professional.
• Large project teams can be utilized effectively to enhance communications, problem identification, and commitment.
• A lack of complete understanding or discussion of FDA data requirements can lead to an overemphasis on some clinical studies and an underemphasis on others; this can result in the conduct of studies not really necessary for FDA approval, with resultant additional costs in time and resources. Regular and careful communications with the FDA, in which the magnitude of the clinical program is precisely defined, can help bypass this potential problem. This means that any FDA (or other regulatory agency) position on data requirements must be thoroughly assessed and proposed studies scrutinized to ensure a clear correspondence between the data requests and individual study protocols.
• Marketing should be included as a member of the project team from the very outset of the clinical development program.
• The identification of new product claims and formulations depends on effective dialogues between clinical research and marketing representatives—dialogues often best conducted through the liaison of the project coordinator. Formal input from Marketing (Statements of Interest, Marketing Needs Report) at the time of clinical plan development can help assure a program that will meet the needs of the Marketing area, as well as address regulatory and medical concerns.

Negotiations of the costs of clinical studies are more carefully monitored through interactions amongst Clinical Research, Project Planning, and Financial Planning groups.

• Every effort should be made to identify all backup candidates for major new compounds early on in the research and development cycle. The additional costs and risks associated with this approach are quite small, and the potential benefits great. In the case of VAS-OTEC®, the almost simultaneous development of a second candidate PRINIVIL®, the combination drug enalapril/hydrochlorothiazide (VASERETIC®), and an intravenous dose form has given Merck a leading position in the world ACE inhibitor market.
• Computerized project management systems can be used to advantage, provided the optimum level of detail tracking is determined. Project Planning and Management has found that following 70-100 activities establishes a good balance between helpful detail and the effort required to both respond to program changes and make activity updates.
• Subsequently, the computerized project management system has been uniquely useful in forecasting resources in a multiproject environment, and in assisting in the examination of what-if scenarios.

Assistance in preparing this article was provided by Beth Keph-art Sulit, a freelance writer.

John E. Engelhart, Ph.D.

A recipient of the Ph.D. degree in Organic Chemistry from the Massachusetts Institute of Technology, Dr. John Engelhart joined the MSDRL Project Planning and Management department in 1980 as Director of Planning for Cardiovascular Drugs. He was subsequently named Director of Planning for Endocrine/Metabolic, Respiratory, Anti-inflammatory, Gastrointestinal and Infectious Disease Drugs. Today, as Director of Project Planning and Management, Dr. Engelhart oversees the planning and decision-making processes associated with some of Merck Sharp & Dohme's largest drug development efforts. Dr. Engelhart is the author of 27 U.S. pa-tents and 11 publications.

Martin F. Malkin, Ph.D.

As the Executive Director of the Planning and Management department of MSDRL, Dr. Martin Malkin is accountable for the activities of some 50 individuals including 14 project coordinators. His association with MSDRL began in 1969 when he joined the Department of Applied Microbiology as a Research Fellow. Following five years of project participation, Dr. Malkin joined the Project Planning and Management department, first as the coordinator for Animal Science projects and later as the Director of Project Planning in Japan. Dr. Malkin obtained his Ph.D. in Biochemistry from New York University, and performed post doctoral work in Biochemistry at Rockefeller University.

R. Richard Rhodes, Jr.

As Director of Project Planning and Management in MSDRL, Mr. Richard Rhodes has strategic responsibility for the development of all Cardiovascular/Renal, Neuroscience, Biological, Ophthalmic and some Endocrine/Metabolic development projects. Previously he was responsible for coordinating the development efforts in Japan for all Merck compounds. Mr. Rhodes initiated the course “Project Management in the Pharmaceutical Industry” presented by the Center for Professional Advancement and is currently Chairman of the project management training committee for the Pharmaceuticals Manufacturers Association. Richard Rhodes has a degree in Industrial Psychology from Lehigh University.

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