Drug Development and Approval Process

1. Drug Development and Approval Process

2. Why New Drug development? • To alleviate the signs and symptoms of new diseases. • To find therapeutic solutions for existing diseases

3. What is drug development? • The entire process of taking a newly discovered compound or drug through regulatory approval to the point of marketing. • During the development, the new drug or the compound should adhere to high standards in the conduct, analysis and interpretation of preclinical and clinical studies for its smooth passage through the regulatory approval phase and eventually to marketing.

4. New Drug Development: For this • a) an established minimally acceptable criteria is required. • b) Create a development plan which will distinguish its desirable to conduct and the necessary to conduct.

5. Designing a clinical trial depends on the specific primary objectives. • Planning, monitoring and auditing – How, what, when, who and were. ( Auditing is done to ensure whether both the PI and monitor are carrying out the function appropriately and the GCP guidelines is followed)

6. What is the Importance of regulatory submission? • Includes consciousness, clarity, correctness (in terms of data provided), completeness and consistency of organization. (Problems must be discussed openly and not buried).

7. The main consumer watchdog in this system is the U.S. Food and Drug Administration's Center for Drug Evaluation and Research (CDER). The center's best-known job is to evaluate new drugs before they can be sold. • The center's evaluation not only prevents quackery, but also provides doctors and patients the information they need to use medicines wisely. CDER ensures that drugs, both brand-name and generic, work correctly and that their health benefits outweigh their known risks.

8. A team of CDER Physicians, Statisticians, Chemists, Pharmacologists, and other scientists reviews the company's data and proposed labeling. If this independent and unbiased review establishes that a drug's health benefits outweigh its known risks, the drug is approved for sale. The center doesn't actually test drugs itself, although it does conduct limited research in the areas of drug quality, safety, and effectiveness standards

9. IMPORTANT STEPS In DEVELOPMENT PROCESS 1) Deciding which compound to develop as New Drug (discovery) To enable this, a discussion must be carried out with the R&D Personnel. And a criteria should be established to discover as a new agent. Research and development criteria • Likelihood of technical success. • Estimate the time to develop the drug to NDA status. • Time to reach go/no-go decision • Anticipated technical development problem. ( Stability of the product)

10. Availability of the drug in desired dosage form • Presence of skills to develop the drug • Degree of medical need for the type of drug. • Medical advantages of the drug compared with alternative therapies. • Actual and potential restriction on the drug use • Cost of development in comparison to predicted third year sales or profit. • Number of potential indication • Any known limitation or problem not covered above.

11. Depending on the answers to the criteria , the company may decide to go all out or to go ahead with a limited program, to develop the agent for certain continues only, to license it to another company or to take a totally different course of action. • Determining the appropriate scope of a drug development plan. A preclinical and clinical programs should be appropriate and well designed. And this is done by developing a plan by the company by eliminating the studies that are not absolutely essential (Lean) and that are essential including all possible consideration and studies (Fat)

12. All the approvals that are too lean and incomplete will not achieve the regulatory approval • And all the studies that are fat, to meet the regulatory requirements not only take extra year to complete but would generate excessive data that would require additional time for processing, analysis, interpretation and report writing. So to balance these two extremes the following decision should be made:- • Determine if it would be reasonable to conduct any of the clinical trials after the drug is marketed.

13. Determine what result would be lost if each study on the list is deleted and which studies are mandatory to conduct. • Review the studies with statistician and could any be abbreviated • Review the clinical plan in detail with the appropriate regulatory affairs. Additional Steps • To evaluate the number and nature of the study conducted on recently approved drug of the same type. • To discuss the issue with knowledgeable consultant

14. To develop alternative step wise plan The master plan must distinguish between studies that are desirable to conduct and studies that are necessary to conduct and whether they are clinical, toxicological, metabolic, pharmacokinetic, or fit other categories of the studies. Although the master plan is blue print for the drug development, the plan must periodically be reassessed and necessary change must be made.

15. 3) Establishing the drug performance during its development Drug that has established the criteria during the drug discovery period -- development phase If it is not established during discovery period it is terminated. To judge each drugs future performance a criteria should be established which should include medical, technical and commercial consideration. If the drug fails to meet these standards then its termination should be considered.

16. The criteria is used to determine whether the drug passes the go/ no-go decision point in phase of its development may be set to a particularly high or low standards. 4)Transfer of a project from preclinical to clinical development and from clinical development to marketing & production Various individuals and functions control the progress decision making about the drug as the drug progress the development pipeline. And minimum number of major transfer is made within the company in the development pipeline when the drug proceeds. Each time the drug get transferred from one department to another, it creates the person or the individual to hold on to it and delay its development.

17. And if the transfer is so soon then its a serious problem that would complicate its development. When the project is transferred from one stage to another stage, if the person taking over the next stage didn't work expeditiously and appropriately, as it take time for the person or the team to be familiar with the details of the product and to undergo the development hence the non-productive time will increase. The development can be speed up if the new leader is member of the team that had been developing the drug. So when the drug enters each new clinical phase (1-5) it takes 5 development leaders plus those in production and marketing.

18. 5) Should the drug also be tested for other indications If the drug is available in appropriate dosage form to treat patient with a particular disease and its formulation is appropriate in terms of stability, bioavailability and other technical consideration. There rises more important questions regarding it possible evaluation for other indication:- • What are the clinical evidence already exist? (that the drug is also effective in patients with other disease and how convenient is the evidence) 2) What animal data already exist ? ( that the drug will be effective in other disease) • What is the medical need of the new drug? ( to treat patient with the disease)

19. 5) What is status of research of the drug to treat the disease for which was originally developed? 6) Dose treating one or more additional disease represents a tangent or part of the agreed on development plan? 7)How will studies on other disease affect resources allocated to the original milestones? 8) What is the marketing perspective on pursuing these other indication? 9) How easy or difficult will it be to obtain regulation approval for the proposed new indication? 10) How expensive will it be in terms of money, time and resources to complete a regulatory submission of each disease?

20. Activities performed on marketed drugs by research and development department Once new agent has reached the point of marketing the major activities performed by technical and regulatory affairs departments are:- Activities performed by research department • Any Research Department • Evaluation of drug MOA • Training of sales representatives • Support marketing medical legal, production and other department with information. • Participating in writing and receiving technical materials • Participate in writing and receiving technical materials for compendia • Answer request for relevant information.

21. Organic Chemistry Synthesis of additional compound for patient protection of marked drugs. Important structural relatives of marked drug must be made to protect them from inevitable intense research conducted in the same chemical area by competitors as well as to seek successor drug. • Medicinal Biochemistry • Measure drug concentration in samples obtained clinical studies that are evaluating new indications.

22. Conduct Biochemical or metabolic studies to evaluate the basis for adverse reaction. • Monitor drug concentration in life threatening situations. • Refine and report on assay methodologies that may be used by outside laboratories • Participate in inter laboratory validation of methods. • Expand the database in specific patients population ( neonates) • Conduct studies to help Develop new formulations.

23. Pharmacology • Investigation of drug- drug interaction that are reports in the literature or to the company • Investigation of newly found therapeutics indication • Investigation of newly found ADRs • Toxicology • Carcinogenicity or other toxicological studies dictated by clinical effects observed before and after marketing • Limited toxicology studies in new formulation

24. Medical • Conduct post marketing trials • Develop new indications • Conduct other trials • Other Departments • Assay of clinical sample of patients participating in clinical studies especially is pursuit of added indication. • Assay of samples from non study patients treated with the drug • Assistance to outside laboratories in setting up assay • Pharmacokinetic studies in special patient group ( dialysis patient ) • Computer assistance for analysis of assay data collected by other laboratories • Resistance studies

25. Activities performed on marketed drug in technical development and regulatory affairs department Library and information service • Monitor published literature for relevant papers • Perform search on published literatures • Prepare bibliography for submission to regulatory authorities Pharmaceutical research and development laboratories • Provide technical support for production • Improve various process • Develop improved formulations or additional dosage form • Conduct Stability studies • Evaluate new packaging components and prepare submission

26. Prepare drug for clinical trial • Validate equipment and process • Prepare documents on formulation/ manufacturing procedures and stability data for annual report to regulatory authorities • Evaluate new equipments/ materials • Participate in establishing release guidelines and revised specification for marketed products Chemical development Laboratories • Provide technical support for chemical production • Search for and develop improved synthetic route • Provide regulatory affairs with documents supporting manufacturing changes • Develop alternative source of key raw materials or intermediates

27. Analytical Development laboratories - Maintain and update development standards and analytical standards for report to regulatory authorities • Convert development standards to analytical standards where applicable • Validate and file modification to assays and other tests procedures with regulatory authorities • Validate and file modification to analytical procedures found necessary as the result of improved formulation • Validate and file modification to the testing methods for raw materials intermediates and bulk drug • Prepare Pharmacopeia – style monograph for the drug and dosage form • Trouble shoot products to minimise problem and back orders.

28. Regulatory affair Department • Submit annual report to the regulatory authorities on each product, describing serious adverse reaction and ongoing clinical trials • Compile, submit and track all submission on marked drugs to the regulatory authorities for new indication for formulations, new route of synthesis, labeling changes and manufacturing control supplements. • Provide support for state / regional formulary activities • Submit adverse reaction report to the regulatory authorities as required by law • Assist the legal department in relevant activities including recalls and liability actions • Maintain official records on all marked drugs.

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