Course Syllabus

BIOT E-205 – Drug Discovery Project Design and Management

Fall Term 2015

Tuesdays 5:30 to 7:30 pm, Science Center 110

If Only Real Life was  That Easy

Paul Ehrlich (1908 Nobel Prize) –            Discoverer of Salvarsan,            the first designed drug

Poppy Plant (Papaver somniferum) –                  Produces Morphine as a                    secondary metabolite

 

Basic Information

BIOT E-205 – Drug Discovery Project Design and Management

Class times: Tuesdays 5:30 – 7:30 pm beginning September 1, 2015

Location: Science Center 110

Instructor: Donald R. Kirsch, Ph.D.

Office Hours: Tuesdays 4:00 to 5:30 pm, 51 Brattle Street room 601 

Course website: https://canvas.harvard.edu/courses/4067  

Contact Information:   Telephone: 617-413-1302 (mobile)

                                    E-mail: kirschdr@gmail.com

Prerequisites

This is a graduate level course that presumes a sophisticated knowledge of biology and chemistry.  Prerequisites include undergraduate courses in cell biology, biochemistry, molecular biology, genetics, pharmacology, organic chemistry, and medicinal chemistry or equivalent (e.g., BIOS E-10, BIOS E-12, BIOS E-16).  Experience in the biopharma industry would be of great value and enable students to obtain maximum benefit from the course. 

Instructional Staff

Donald R. Kirsch, Ph.D. – AB Rutgers College (1972), AM, PhD Princeton University (1978), certificate program in technical management from Stanford Business School (1991) – >30 years of research experience in the biopharma industry (Squibb, Bristol-Myers Squibb, Cyanamid/Lederle, American Home Products → Genetics Institute/Wyeth) - CSO Cambria Pharmaceuticals.  Dr. Kirsch is an author of over 50 scientific research papers and review articles and an inventor on 25 patents and patent applications. 

Course Description

The course outlines the basic principles underlying the design of drug discovery campaigns and the management of such programs without formal authority (matrix management). The course acquaints the student with current drug discovery practices in the biotechnology and pharmaceutical industries. The steps in the process are presented and strategic considerations are discussed through case studies. The course should help prepare students who already have a background in the scientific disciplines underlying drug discovery (cell biology, biochemistry, molecular biology, genetics, pharmacology, organic chemistry, and medicinal chemistry) to take on the design and management of research programs aimed at the discovery of new or improved pharmacological agents. The course is not specific to one therapeutic area but rather provides information common to drug discovery in all therapeutic areas.  

There will be parallel discussions on science and management.  In my opinion every clinically approved drug was discovered in a unique way.  As a result, and heterodox for science instruction, the case studies teaching method will be used.  There is no best or correct drug discovery practice to be taught.  The best science produces the best drugs, but must be enabled by effective management.  The students will bring much experience and knowledge and in aggregate probably know more about this than the instructor.  The course thus will be in good part taught using the Socratic Method and class time will be devoted to discussion. 

Course Aims and Objectives

Many of the research staff in the biopharma industry will at some point move from bench research to the management of drug discovery programs.  The academic research model tends to be that of a lone researcher, toiling away at his/her lab bench in search of the truth.  In contrast, industrial research is highly collaborative and needs to be collaborative because of the large number of diverse skills required to discover a new drug and bring it to the clinic (cell biology, chemistry, pharmacology, physiology, medicine, etc., etc.).  There is also a distinction between goals.  In academic science one searches for the single correct answer to one’s research problem.  In industry one looks for a medicine, but there are probably dozens of possible drugs to treat any disease of interest.  The goal is to find just one of these and to focus all efforts on that single possibility. 

Therefore, a skill not commonly taught in academia is to integrate diverse disciplines into a team with a common goal and purpose.  This requires both technical skill (although recognizing that no one can master all of the diverse disciplines needed for project success) and management skill.  Both the science of drug discovery and good management practices will be presented and discussed.  The goal of the course then is to facilitate the transition of the student from researcher to program manager.    Even if your goal is not to become a drug discovery program manager, the course should instill an appreciation of the obstacles involved in project management and make the student a better team member. 

Course Policies and Expectations

Since the class in aggregate probably knows more about the topic than the instructor, it is important for everyone to attend and participate.  Your absence not only affects your own learning, but potentially the education of the entire group.   As a practical matter, your observations of the class working effectively or ineffectively as a team will provide concrete data on team dynamics and a model for future use in what behaviors are desirable or undesirable in working teams.  Your attendance will help make this team successful, as you would like future members of your team to contribute to your success. 

The fundamental job of the project manager is to design the drug discovery program, submit it to management for approval and then implement the approved project.  The assignments reflect this task and are in effect job simulations.  Due dates are toward the end of the semester to maximize the amount of information available to the student prior to completing the assignment.  As a consequence, feedback on performance during the term will be limited, although this will to some degree be revealed as a consequence of class discussion.   Therefore students will need to have a high degree of self discipline to monitor their ongoing mastery of the material.  The first written assignment will be due on November 11 and the final assignment on December 16.  As in actual industry practice, excuses are not acceptable for missing critical deadlines.  If you miss a critical deadline in industry, this will probably be a good time to start revising your CV.  You will have ten weeks to put the first assignment together.  Start early.  Also as a result, if you do poorly on the first assignment it will unfortunately be extremely difficult to redeem yourself.  There will also be two take home quizzes to help incentivize students to master the classroom material. 

Materials and Access

There are no textbooks for drug discovery project design and management in the same sense that there are textbooks for organic chemistry or cell biology.  The closest books I could find are “Drugs from Discovery to Approval”, Rick Ng, Third Edition, Wiley Blackwell, 2015 and “Drug Discovery and Development: Technology in Transition”, Raymond Hill and Humphrey Rang, Second Edition, Elsevier Health Sciences, 2012.  Each has its strengths and weaknesses and you should buy at least one of these.  I suggest that you select your book based on your own scientific strengths and weaknesses as well as your professional interests.  For the management portion of the course all students should buy the Universal Concepts Guide and Self-Perception Questionnaires – Tracom Group (http://www.tracomcorp.com/wp-content/uploads/2014/04/SocialStyle-InfoSheet-UniversalSocialStyleConceptsGuideandSelfPerceptionQuestionnaires.pdf).  This is a Carl Jung/Myers Briggs type tool that will help you identify your behavioral style and provide pointers on how to identify and more productively deal with those with differing behavioral styles.  “Goodman and Gilman's The Pharmacological Basis of Therapeutics”, Twelfth Edition, Brunton, Chabner and Knollmann, McGraw Hill Medical, 2011 is the bible of pharmacology and a key reference book for the field.  I think anyone who is serious about having a career in drug discovery should own a copy.  For those particularly interested in financial aspects of the drug discovery process I would recommend “Analysis for Financial Management “, Eleventh Edition, Robert C. Higgins, Mcgraw-Hill/Irwin Series in Finance, Insurance, and Real Estate, 2015.  This book covers the basics of finance, is a good reference for budgeting managers and has a very good overview of financial decision making.  Lastly, the case study presentations will be based on papers from the scientific literature.  These references are largely available from the Harvard Medical School Countway Library, but I will try for everyone’s convenience to provide access to pdf copies when possible. 

 Assignments and Grading Procedures

 

Students’ performance will mainly be assessed on the basis of two written assignments.  1) The first assignment will be to design a drug discovery campaign: select an underserved disease, describe the clinical need and financial viability of the proposed new drug and select a drug target that could provide improved clinical treatment for the disease.  Then describe how the target will be validated, how lead compounds acting on the target will be identified, how these lead compounds will be optimized and the criteria you will use to select a clinical candidate compound.  Alternately the student could start with a clinical lead compound from the literature (a drug for which no clinical studies have been published), summarize the properties of the clinical candidate drug and then describe the clinical program needed to bring the drug to FDA approval including standard and ‘custom’ elements of the clinical transition program needed to support the proposed clinical program.  Design the three clinical phases to support clinical outcome goals that will provide adequate power to achieve statistical significance.  Include number of patients, patient recruitment, outcome measures and trial design (randomized, case controlled, etc.).  2) In the second assignment, utilizing the drug discovery or development campaign from the first assignment, the student will provide an estimated timeline for the campaign, the resources (type and quantity) needed to carry out the campaign and a budget for the program.  Also provide a return on investment estimate for your financial colleagues.  This second assignment should cover both the discovery and the clinical development segments of the campaign.  

There will also be three open book/take home quizzes. 

Grading will be largely based on the quality of the above assignments with the first assignment accounting for 50% of the grade, the second assignment 25% and class participation/quizzes 25%. 

Academic Integrity

Any material submitted to meet course requirements is expected to be the student’s own work.  For example, if you are employed in industry it would be a violation of policy to use an ongoing or abandoned project from your company as the basis for the assignment.  Similarly, a project described in the literature should not be used, but drug discovery projects described in the literature can be cited in support of your own ideas.  That is to say, work in the literature can be used if properly cited and not plagiarized.  Similarly, work submitted for other courses should not be resubmitted for this course. 

You are responsible for understanding Harvard Extension School policies on academic integrity (www.extension.harvard.edu/resources-policies/student-conduct/academic-integrity) and how to use sources responsibly. Not knowing the rules, misunderstanding the rules, running out of time, submitting "the wrong draft", or being overwhelmed with multiple demands are not acceptable excuses. There are no excuses for failure to uphold academic integrity. To support your learning about academic citation rules, please visit the Harvard Extension School Tips to Avoid Plagiarism (www.extension.harvard.edu/resources-policies/resources/tips-avoid-plagiarism), where you'll find links to the Harvard Guide to Using Sources and two, free, online 15-minute tutorials to test your knowledge of academic citation policy. The tutorials are anonymous open-learning tools. 

 

Accommodations for students with disabilities

The Extension School is committed to providing an accessible academic community. The Disability Services Office offers a variety of accommodations and services to students with documented disabilities. Please visit www.extension.harvard.edu/resources-policies/resources/disability-services-accessibility for more information. 

Course Schedule

1st Lecture, September 1 - Pharmacology basics and introduction to behavioral styles

 

Objectives and Rationale – The beginning of the first class will be devoted to our meeting and getting to know one another.  The initial science lecture will be devoted to bringing everyone up to speed on the fundamental general principles of pharmacology.  The initial organizational behavior lecture will present the Carl Jung-based behavior model we will be using to help us improve workplace effectiveness.  For homework students will complete a self scoring questionnaire that will identify their behavioral style and take an open book quiz on the material covered in the lecture.  We will also discuss the broad rationale for the course and how the individual component topics contribute to the overall learning goals.  

 

2nd lecture, September 8 – Pharmacological receptor types, brief overview of finance and discussion of the Tracom behavioral style model with coaching on how to recognize behavioral types – THE FIRST TAKE HOME QUIZ SHOULD BE HANDED IN TODAY.   

 

Objectives and Rationale – We will discuss the major pharmacological receptor types and that these proteins are particularly susceptible to pharmacological manipulation.  While financial analysis is not required for this course, many prior students have asked for discussion on this topic.  This will just cover the very basics, but this could possibly serve as a springboard for additional study on your own.  We will have our first full session on the Tracom behavioral style model, provide students an opportunity to reflect on the own behavioral style and provide initial coaching on how to recognize behavioral types

 

3rd lecture, September 15 – Evolution of the contemporary drug discovery process and discussion of the Tracom behavioral style model with coaching on how to recognize behavioral types – THE SECOND TAKE HOME QUIZ SHOULD BE HANDED IN TODAY.   

 

Objectives and Rationale – We will review the evolution of the contemporary drug discovery process to provide prospective on the current state of the industry as well as to provide background for future discussions and the first assignment.  We will continue working on the recognition behavioral types and, if possible, have one or more visitors with whom you can interact to determine their behavioral styles.  We will begin to discuss how to use the behavioral style model to improve work relationships.  Each student will select a specific difficult relationship in their work environment to which the model will be applied.        

 

4th lecture, September 22 - Drug discovery process – target identification and validation, screen design and implementation, hit to lead (or alternate means for lead generation), lead optimization, clinical candidate selection and we will use behavioral styles as a model to more effectively work with others.  The class will explore how to utilize the model to improve difficult relationships at work and will discuss behavioral versatility and its value in the workplace. 

 

Objectives and Rationale – We will discuss the drug discovery process as it exists today going over each of the individual steps in the process.  While there is no one correct or best way to discover a new drug, this discussion will at least provide an overview on how the drug discovery business is generally conducted.  We will explore how to improve work relationships by modifying our behavior to best interact with those having differing styles. Students will establish improvement goals for themselves that will be discussed during the next session          

 

5th lecture, September 29 - Drug development process – clinical transition, dealing with regulatory authorities, IND requirements, clinical phase I, clinical phase II, clinical phase III, NDA requirements, post launch monitoring and discuss our behavior style improvement goals.  This will also be the first class to explore general management topics (to be continued in future classes as needed) – leadership, management systems, relations with staff, dissemination of information, team relationships (team vs. working group), organization types, decision making model, authority and delegation, obtaining commitment, conflict management, corporate culture, mentoring and compensation models.  Following class students should submit to the instructor via e-mail their proposed first assignment disease target and therapeutic target for discussion at the next class session. 

 

Objectives and Rationale – This is a parallel lecture to the proceeding session but focusing on clinical drug development instead of pre-clinical drug discovery.  This lecture will conclude our formal discussions on behavioral styles and initiate a series of discussions on basic management topics.  There is a long list above which cannot be covered in a single session.  We will therefore cascade topics to future class meetings.  Also, at this point everyone should be very close to the final selection of a target for his or her drug discovery program for the first written assignment.  Your targets will be the basis for the next lecture to be conducted in a ‘clinic’ format. Please e-mail your selected disease and drug target to the instructor no later than Monday, October 6. All targets will be discussed and critiqued at the next, 6^th lecture, session.  You should use the critiques to revise and optimize your targets as needed and incorporate these changes when preparing the first written assignment.            

 

6th lecture, October 6 - Target manipulation strategies (basically Goodman and Gilman reorganized from a drug discovery perspective) and continue discussion of general management topics. 

 

Objectives and Rationale – The Goodman and Gilman textbook is the traditional bible of pharmacology.  However, it is organized using a physiological and medical framework, an excellent approach to training physicians.  Contemporary drug discovery is based on a biochemistry, cell biology and molecular biology.  I have therefore rearranged the information as someone in drug discovery would like to see it.  We will fit student drug discovery targets into this format and discuss them in class.  Precedent is the best way to predict the success of a drug discovery campaign. We will review all student targets relative to existing drug targets.  Students may wish to select an alternate target in cases where there is little of no precedence for their original target.  For homework students will complete an open book quiz on general pharmacology.  Management topics carry over from the prior session. 

 

The next nine lectures will be case studies.  This is obviously highly heterodox for science pedagogy, which stresses the broad concepts and principles that have emerged from the scientific endeavor rather than the process by which individual discoveries were made.  Based on my belief that there is no best or correct practice for drug discovery, we are left with trying to learn from the successes and failures of our predecessors.                

 

Case studies

 

7th lecture, October 13 - Random screening – ivermectin (Mectizan), discussion of related management issues and as needed continue discussion of management topics - THE THIRD TAKE HOME QUIZ SHOULD BE HANDED IN TODAY. 

 

Objectives and Rationale – In the twenty first century we would like to do everything in a completely rationale way.  This is not always the best path to a breakthrough medicine, illustrated by ivermectin.  We will in parallel discuss the management issues and practices that enabled the discovery of ivermectin and carry over management topics from the prior session.

 

8th lecture, October 20 - Careful clinical observation – clorpromzaine (Thorazine) to aripiprazole (Abilify), discussion of related management issues and as needed continue discussion of management topics

 

Objectives and Rationale – How do you find a medicine for a disease with an unknown molecular etiology and whose underlying character is unique to humans and as a result cannot be modeled in animals with any really meaningful way?  Yet, counter intuitively we have reasonably effective medicines to treat schizophrenia.  Many things in drug discovery cannot be planned in advance, including the discovery of chlorpromazine and later generation related compounds.   We will discuss the management issues and practices around the discovery of the neuroleptic antipsychotics and as needed carry over management topics from the prior session.

9th lecture, October 27 - Improving on empirically discovered drugs - sitagliptin (Januvia), discussion of related management issues and as needed continue discussion of management topics

Objectives and Rationale – As scientists we would like to believe that a rational approach will always beat empiricism.  This is not always true, and finding an anti-diabetic agent superior to a series of drugs previously discovered by pure empiricism turned out to be more difficult than expected, as illustrated by sitagliptin.  We will in parallel discuss the management issues and practices that supported the discovery of sitagliptin and carry over management topics from the prior session.

 

10th lecture, November 3 - Me too: from first to best in class – lovastatin (Mevacor) to atorvastatin (Lipitor), discussion of related management issues and as needed continue discussion of management topics

 

Objectives and Rationale – In science we are taught the value of being first.  Everyone knows that Stanley Prusiner is the father of prions, but do we know the names of the people who confirmed his Nobel Prize winning discovery?  First is not however always best in drug discovery.  The first drug in a class often paves the way for the best drug as illustrated by lovastatin and atorvastatin.  We will in parallel discuss the management issues and practices around the discovery of these cholesterol lowering drugs and as needed carry over management topics from the prior session.

 

11th lecture, November 10 - Protein therapeutics – etanercept (Enbrel), discussion of related management issues and as needed continue discussion of management topics – FIRST WRITTEN ASSIGNMENT DUE

 

Objectives and Rationale – The earliest protein therapeutics were replacement therapies (e.g., insulin).  Current protein therapeutics are disease modifying agents and the discovery of etanercept is a good contemporary example of this approach.  We will in parallel discuss the management issues and practices that enabled the discovery of etanercept and carry over management topics from the prior session. WARNING – THE KEY FIRST ASSIGNMENT IS DUE TODAY!!!!

 

12th lecture, November 17 - Rational design – captopril (Capoten), discussion of related management issues and as needed continue discussion of management topics

 

Objectives and Rationale – Captopril is a great early example of rational design in drug discovery.  The drug was however almost abandoned because of lack of commercial support.   We will discuss the management issues and practices around the discovery of captopril and as needed carry over management topics from the prior session. 

 

13th lecture, November 24 - Starting with an inactive lead – aztreonam (Azactam), discussion of related management issues and as needed continue discussion of management topics

 

Objectives and Rationale – Leadership is an essential component for success in drug discovery.  Could you talk your boss into giving you substantial resources to pursue something that was obviously inactive?  Richard Sykes did and his drug, aztreonam, has been helping patients for many years.  We will discuss the management issues and practices around the discovery of aztreonam and as needed carry over management topics from the prior session.

 

14th lecture, December 1 - Side effects can be good effects – sildenafil (Vaigra), discussion of related management issues and as needed continue discussion of management topics

 

Objectives and Rationale – The path to clinical success is not a straight or easy one.  The best drug hunters turn lemons into lemonade.  We will discuss the management issues and practices around the discovery of sildenafil and as needed carry over management topics from the prior session.

 

15th lecture, December 8 - Bait and switch in drug development - ezetimibe (Zetia), discussion of related management issues and as needed continue discussion of management topics

 

Objectives and Rationale – There are many surprises in drug discovery.  The best drug discovers proceed to produce a therapy even if their underlying premise is proven wrong.  Ezetimibe is an example of a drug that works, but for an unintended reason.  If it works in practice you should not devote undue worry to making it work in theory.  We will in parallel discuss the management issues and practices that enabled the discovery of ezetimibe and as needed carry over management topics from the prior session.

 

16th lecture, December 15 - Careful clinical observation reprise – imipramine (Depranil) to fluoxetine (Prozac), discussion of related management issues and as needed continue discussion of management topics – SECOND WRITTEN ASSIGNMENT DUE

 

Objectives and Rationale – Another example of the discovery of a medicine for a disease with an unknown molecular etiology and whose underlying character is unique to humans: clinical depression.   We will discuss the management issues and practices around the discovery of the tricyclic antidepressants and their follow on therapeutics, the SSRIs.  As needed, we will cover any remaining management topics. WARNING – THE SECOND AND FINAL ASSIGNMENT IS DUE TODAY!!!!

 

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