Clinical trial phases, requirements and regulations
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An intensive overview of various phases of clinical trial, their aims & objectives with various characteristics of each phase
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Clinical trial phases, requirements and regulations
- 1. DR. SIDDHARTHA DUTTA MAMC, NEW DELHI
- 2. Introduction Drug Discovery & Development Phases of clinical trial-O, I, II, III, IV Pre-requisites & Objectives Phase 5 Conclusion
- 3. First controlled clinical trial on 12 Sailors -Scurvy Clinical Trial by James Lind 1747 – Lind’s study comparing the use of limes and oranges in the treatment of scurvy 1948-First randomized controlled clinical trial in Medical Research Council TB Unit, Brompton Hospital, UK First use of a randomized control group: streptomycin James Lind
- 4. CLINICAL TRIAL “CLINICAL TRIAL” is a systematic study of new drug in human subjects to generate data for discovering and/or verifying the clinical, pharmacological and adverse effects with the objective of determining safety and efficacy of the new drug.
- 5. Criteria Last century Present era Animal use Frequent Relatively less Ethical Considerations Less stringent More Stringent No. of Compounds explored Less More No. of Targets explored Less More Terminology Drug discovery Drug development5
- 7. DRUG/DEVICE TRIALS- A CUMBERSOME PROCESS Target a subset of the population, means not everyone can participate Appropriate patients and obtain their consent, especially when they may receive no direct benefit Requires patients to have unusual combinations of disease characteristics For chronic conditions like cancer, it takes months, if not years, to monitor efficacy For drugs that are not expected to have a strong effect recruiting enough patients to test the drug's effectiveness can take several years
- 8. New drug ready to be studied in humans a Notice of Claimed Investigational Exemption for a New Drug (IND) must be filed with the FDA It includes :- 1. Info. on the composition and source of the drug 2. Chemical and manufacturing information 3. Animal studies data 4. Proposed plans for clinical trials 5. Names and credentials of physicians who will conduct the clinical trials 6. A compilation of the key data relevant to study of the drug in humans that has been made available to investigators and their institutional review boards
- 11. Exploratory, first-in-human trials conducted in accordance with the USFDA 2006 Guidance on Exploratory IND Studies Limited human exposure No therapeutic or diagnostic intent Assists in GO vs. NO GO decision early in development process Single sub-therapeutic dose of the NCE to gather preliminary data on the agent's PK/PD before initiating phase 1 testing
- 12. Phase 0/ Exploratory IND study Microdose study PK in humans Imaging techniques Pharmacological dose study PK/PD in humans Requires more preclinical data
- 13. 10 to 15 healthy volunteers Limited dosing duration ≤ 7 days Very low doses (1/100th of estimated human dose or max. of 100 µg total dose of candidate drug) No data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect Phase 0 clinical trial are not mandatory
- 14. ADVANTAGES DISADVANTAGE S • No data on safety or efficacy • Ethical concerns PK & PD on human subjects Elaborate animal studies & costly phase I human trials could be avoided for candidate drugs Regulatory flexibility Data helps to prioritize promising compounds Useful in more precise selection of doses for & modify phase 1 design
- 15. PHASE 1
- 16. 25-100 healthy volunteers First in Human studies Extrapolation of animal data to humans Phase 1 Dose escalation studies
- 17. OBJECTIV ES Assess tolerance and Safety PK/PD Explore drug metabolism & interactions Route of administratio n Safe clinical dosage range in humans
- 18. FIH calculatio n from animal studies Phase 1 Clinical Pharmacaolo -gy Units CPU/ CRU Full-time medical experts & staffs Full time biochemi cal & pathologi -cal labs
- 19. Phase 1 Single ascending dose Multiple ascending dose Food effect relationship
- 20. Single ascending dose Phase 1a • Small group of subjects given single dose of drug and observed for a period of time • If PK data is in line with predicted safe values, the dose is increased in a new group of subjects • Continued till maximum tolerated dose (MTD) is defined Multiple Ascending dose Phase 1b A group of subjects receives multiple low doses of the drug Samples (of blood and other body fluids) collected at various time points and analyzed Gives better understanding of PK/PD & safety of the drug
- 22. REGULATIONS WITH PHASE 1 Schedule-Y (2005 amendment) of the Drugs and Cosmetics Rules made parallel trials possible in India Documents to be submitted before commencing phase I trials 1) All documents of pre-clinical data. 2) Plans, protocols and CRF ’s for phase I studies. 3) Name, address and bio-data of investigator. 4) Agreement from the sponsors to inform the drug controller of any adverse reaction’s occurring during ongoing animal/human studies. 5) Nature of ‘informed consent’ 6) Agreement to submit annual progress report.
- 23. Assessment of data and expert consultation are done to decide the role of drug in adverse event and study continuation Serious toxicity is rare and needs judgment for proceeding Interpretation, of clinical and lab deviations, from normal range needs to be done, and within subject comparison, of data is mandatory
- 25. Therapeutic exploratory trial 100-300 Patients Confirm the hypothesis conceptualised Dose response determination Determine potential end points Types of patients and specific indications Determine of target population Determine dose regimen Safety Drug Interaction s Efficacy
- 26. Series of doses of varying strengths may be used in phase II trials to determine the effective dose, dosing regimen frequency and duration Comparator –standard treatment or placebo Controlled Single Blind RCT End points :- 1. Definitive end point Measures drug effect directly—cancer(mortality), Pain relief (analgesic), HTN(stroke) 2. Surrogate end point Predictive of the definitive end point --Reduction in tumor size (anticancer) or cancer-associated proteins p53, TGF-α and BP or cholesterol level in HTN
- 27. Phase 2a How much drug should be given Phase 2b How well is the response to the dose Phase 2 27
- 28. Phase 2 A Proof of concept Pilot trials Up to 200 patients Therapeutic efficacy Single blind, parallel group Dose response & dose range for phase 2b
- 29. Phase 2 B Pivotal trial 200-500 patients Optimal dose & dosing regimen Confirm efficacy Single/ Double blind Patient population defined
- 30. PHASE III
- 31. Therapeutic confirmatory trial Multicenter RCT 1000-5000 patients Expensive, time- consuming Double-blind cross overPhase 3 Efficacy at various stages of the disease Extensive Safety & Efficacy testing Comparison with Gold Standard Rx
- 32. Pt. grp. (randomi zed) Week 1 Week 2 Week 3 I Standard drug Placebo New drug II Placebo New drug Standard drug III New drug Standar d drug Placebo
- 33. Determine dosage schedule, that demonstrates adequate efficacy and safety Identify disease subtype, where drug is effective (or ineffective) Comparison PK/PD with other standards Evaluation of special population (e.g. elderly, renally impaired, etc)
- 34. Peri-approval studies Not a part of regulatory dossier Study drug vs. market leader Cost value arguments Assess QOL & Pharmacoeconomics studies
- 35. PHASE IV
- 37. Phase 4 PMS Large simple trial Pharmaco- epidemiolo gical studies Pharmaco- economic studies Investigato r initiated research Drug utilizatio n studies Case control studies
- 38. Non-interventional study mandated by regulatory authorities to verify the safety, tolerability and effectiveness of a marketed drug in a particular population Open studies where unlike pre-marketing studies, no strict inclusion & exclusion criteria, but governed by the permissible indications and contra-indications of the drug as stated in prescribing information PMS studies exemplify the difference b/w EFFICACY and EFFECTIVENESS PSURs SUSAR(Serious and unexpected suspected adverse reactions)
- 39. Describe how a drug is marketed, prescribed, and used in a population, and how these factors influence outcomes, including clinical, social, and economic outcomes These studies provide data on specific populations, such as the elderly, children, or patients with hepatic or renal dysfunction, often stratified by age, gender, concomitant medication, and other characteristics. DUS have been used to describe the effect of regulatory actions and media attention on the use of drugs, as well as to develop estimates of the economic burden of the cost of drugs. DUS can be used to examine the relationship between recommended and actual clinical practice These studies can help to determine whether a drug has the potential for drug abuse limitations include a lack of clinical outcome data or information of the indication for use of a product.
- 40. PHASE V Pragmatic trial/ translational research Designed to test interventions in the full spectrum of everyday clinical settings in order to maximize applicability and generalizability. Research question- whether an intervention actually works in real life?? Moves from the researcher’s bench to the patient’s bedside Idea is to analyze the data of the drug which is in wide spread use to maximize its benefits so that it can be used for the betterment of broader sections of community It is used to signify the integration of a new clinical treatment into widespread public health practice
Notas do Editor
- In the1700s, scurvy was a particularly vexing problem on the long voyages across the Atlantic Ocean. reviewed the existent literature of the time. In so doing, he found a report from 1600 that stated ‘1 of 4 ships that sailed on February 13th, 1600, was supplied with lemon juice, and almost all of the sailors aboard the one ship were free of scurvy, while most of the sailors of the other ships developed the disease. 1747, while serving as surgeon on HMS Salisbury, he carried out experiments to discover the cause of scurvy, the symptoms of which included loose teeth, bleeding gums and hemorrhages. 6 pairs, each group different additions +basic diet. Some were given cider, seawater, mixture of garlic, mustard & horseradish. spoonfuls of vinegar, and the last two oranges and lemons One of the two recovered quickly and was fit for duty after 6 days, while the second was the best recovered and was assigned the role of nurse for the remaining patients Bradford Hill-study of streptomycin in pulmonary tuberculosis
- conducted to allow safety and efficacy data for new drugs or devices. can only take place once satisfactory informn is gathered on quality of the product and its non-clinical safety, and Health Authority/Ethics Committee approval can vary in size from a single center in one country to multicenter trials in multiple countries
- CT- small part of the research that goes into developing a new treatment. Potential drugs, first discovered, purified, characterized, and tested in labs, (in cell, and animal studies) before ever undergoing clinical trials. about 1k potential drugs are tested before 1 reaches CT
- (meaning a large number of patients must be recruited to observe any effect), (i.e., getting statistical power) It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because the study drug is not yet proven to work, or the patient may receive a placebo). Clinical trials that do not involve a new drug usually have a much shorter duration
- Almost 40% of Phase 1 failures are thought to be due to PK issues Human Microdosing aims to reduce the resources spent on non-viable drugs Using human models rather than relying on the animal data helps us to confirm end points
- label a candidate drug-radioisotope carbon-14, and then administer the compound to human volunteers, at levels typically about 100 times lower than the proposed therapeutic dosage. (f1, to 100 mcgrams). As only microdose levels of the drug are used, analytical methods are limited. Extreme sensitivity is needed. AMS, i.e. accelerator mass spectrometry is the m/c method for microdose analysis. sensitivity of picogram to attogram range, and AMS still continues to be more sensitive than the most sensitive LC/MS/MS machines Exploratory FIH studies at pharmacologic dose have particular utility where the PK/PD profile will facilitate informed decision making and can offer either early program termination or rapid progress to phase II
- Developed by FDA & EMA as “cost-cutting” tools They are case to case based. no concept of Phase 0 or any other equivalent of an Exploratory IND in Indian regulation. particularly oral bioavailability and half-life of the drug Pharmacok worked out using AMS with radiolabelled drug/LC-MS to measure ultra low drug levels
- Shorten drug development timeline by reducing chances of failure in subsequent phases No benefit to participants-where as reqrd to give blood samples/ biopsy for PK/PD analysis
- Human pharmacology studies Test drug is too toxic to be tested in healthy volunteers E.g anticancer drugs, HIVbiologics Therapeutic range/ratio is too narrow to test (e.g. Antiarrhythmic) Dose in patient > Normal Volunteers can tolerate (e.g. Neuroleptics) PK issues are addressed metabolism of a newer anti epileptic whose microsomal enzymes are already induced by an anti epileptic drug. dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer Single ascending dose & multiple ascending dose studies
- Ex: 1) dose tolerance studies 2) SAD/MAD PK/PD studies 3) drug interactions Safety (Drug affects CV, hepatic or renal functions adversely) Tolerability (Drug produces unpleasant symptoms like headache, nausea & vomiting) whether humans & animals show significant pharmacokinetic differences Whether deficiency in drug effect is due to lack of absorption / faster elimination)
- Begin with 1/5th or 1/10th of MTD in animals & calc. it for 70 kg body wt.) Detect any predictable toxicity Volunteers are paid an inconvenience fee for their time spent
- Maximum tolerated dose Nature of adverse reactions that can be expected Preliminary characterization of the drug Accumulation of parent drug/ metabolites Bioavailability in presence of food Drug - drug interaction ( mostly parallel to phase II)
- MAD- dose and dosing frequency r chosen in order to attain therapeutic drug levels of drug in the blood which is maintained in steady state level foe several days to assess the safety parameters If accumulation on multiple administration Single blinded placebo controlled to determine whether effects observed are due to the study drug or environmental conditions & to allow informed decision on dose escalation, with safety and PK data being available for investigator review. Food effect –fast and fed state, standard diet given , act as their own control “Schedule of drug administration in Phase I is determined from the preclinical testing” “Investigator(s) report all sae to the Sponsor -24 hours and to the EC within 7 working days of their occurrence”. Sponser- 14 calendar days would be communicated to the local regulatory authority & other PI
- Cmax Peak drug &/or metabolite concentration Tmax Time to peak drug &/or metabolite conc. AUC0-∞ Area under conc.-time curve e.p. to inf. AUC0-T AUC calc. to a specific time point T T1/2 Time taken for level of drug to dec. by 1/2 VD Volume of distr. CL Clearance MRT Mean residence time (Avg. time a drug molecule rem. In body after rapid i.m. injection)
- Drugs and Cosmetics Rules, phase I trials are not normally permitted for foreign companies and is usually reserved for the new drug substances discovered in India. Regulatory fees payable to the DCGI’ s office for reviewing submitted documents is Rs. 50,000/- for phase I studies. Application is to be submitted to the Drugs Controller General (India) If investigational drug is responsible for an adverse event, subsequent administration has to be prevented
- major challenge in new drug testing
- Main purpose Gather evidence that drug has effects suggested by preclinical trials designed to assess how well the drug works, as well as to continue Phase I safety assessments.
- Drug studied for 1st time in pts. with target disease risk-benefit profile has to be assessed, as to whether the trial should use placebo or standard treatment, to ensure the subjects’ well being is not compromised during the tria Specific clinical endpoints or markers are used to assess interaction of drug and disease
- with IIb, being an extension to the safety and efficacy studies assessed in IIa.
- Primary goal: To determine the evidence of therapeutic efficacy & safety. Pilot trials: Dose response determination, determine dose regimen and determination of target population. Establishment of dose range for more definitive therapeutic trials in phase Iib Proves primary hypothesis Efficacy Effect Size Adverse events (ADR of special interest) Biomarker profiling
- Pivotal- it can make or break the success of the drug Test different doses and find optimal dose Type of patients more responsive to treatment. Placebo/Active controlled criteria Tight inclusion and exclusion criteria Multi-centre /Multinational trial Dose-response Frequency Additional ADR Identifying confounding factors
- Out of all the drugs which enter phase 1only 1/3 of drugs ever make it to Phase III clinical trialsal most 80% of those that do enter Phase III trials move on to Phase IV trials. Extended Clinical Trials- confirm efficacy in large pt grp difficult trials to design and run, especially in therapies for chronic medical conditions. Conducted in patients in whom the drug will be eventually intended. Eg. Mild Moderate severe Inclusion and exclusion criteria relatively relaxed Different dosages and combinations with other drugs
- Subjects: large. Trial design: open level or single or double blinded. Multicenter. Testing different stages of the disease indication. Dosage forms , formulation Different routes.
- Conducted predominantly for marketing purposes Comparator is market leader-in hope to achieve a benefit over & above the existing drug This enables marketing & sales group to maximize the performance after launch Phase 3b: Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. i.e. Antiretroviral, Anticancer etc. .
- Inclusion/exclusion criteria are not stringent, wider patient population. Interaction with other drug if not tested earlier Rare adverse effects Eg. Immunogenicity. Long Term adverse effects on larger population for longer period. cerivastatin ,troglitazone rofecoxib New use- detected by a chance discovery aspirin antiplat Route- nimusulide rectal Special population groups such as pregnant women
- 1 mandated by RA to be conducted as observational studies in a naturalistic setting - PMS 2 Phar epidemio- outcome research studies- morbidity/mortality studies cost-minimization analysis, cost-benefit analysis, cost-effectiveness analysis or cost-utility analysis. Quality-adjusted life years DUS- how a drug is marketed, prescribed, used in populn and how these factors influence clinical, social and economic outcomes Case-con- retrospective evaluation- rare SE eg- thrmphlebits/TE by ocp RA now insisting on sponsers to carry premarketing p 3 which mimics real world scenario- greater confidence before approval adv- minimize drug withdrawl disadv- delay launch, costly drug
- Efficacy is judged within the controlled environment of a clinical trial with strict inclusion and exclusion criteria and close monitoring and ensured compliance. Effectiveness is the real test of a drug when it is used in a much larger population, with varied organ system function, concomitant drugs and where monitoring and compliance are not always ensured. With these confounding factors when drug shows its effect its effectiveness (SUSARs) are reported to RA on a continual basis and non-serious ones are compiled and reported periodically.
- DUS can be used to determine if a product is being used in these populations. From these studies denominator data can be developed for use in determining rates of adverse drug reactions drug abuse by examining whether patients are taking escalating dose regimens or whether there is evidence of inappropriate repeat prescribing
- clinical trials typically exclude from study participation women who are pregnant or breastfeeding; therefore, PMS is the only means of obtaining information on mutagenic and teratogenic effects of drugs in humans. Other special populations that benefit from PMS include the elderly and patients with multiple comorbidities. Like pregnant women, patients who are very old or very sick are excluded from premarketing trials. Phase IV trials include additional drug-drug interaction(s), dose-response or safety studies and trials designed to support use under the approved indication(s), e.g. mortality/morbidity studies, epidemiological studies etc. all phase IV studies require permission from DCGI office. These trials go beyond the prior demonstration of the drug’s safety, efficacy and dose definition.
- Not all Phase IV studies are post-marketing surveillance (PMS) studies but every PMS study is a phase IV study. Phase IV is also an important phase of drug development. In particular, the real world effectiveness of a drug as evaluated in an observational, noninterventional trial in a naturalistic setting which complements the efficacy data that emanates from a pre-marketing randomized controlled trial (RCT).True safety profile of a drug is characterized only by continuing safety surveillance through a spontaneous adverse event monitoring system and a post-marketing surveillance/non-interventional study. Surveillance of spontaneously reported adverse events continues as long as a product is marketed. And so Phase IV in that sense never ends.
- Not a legal/std terminology None of the stand guidance documents mentions about this Research aimed at enhancing the adoption of best practices in the community research findings like Community clinical epidemiology, health services (outcomes) research, Cost-effectiveness of prevention and treatment strategies Basic results in gen knwledg and understanding of nature and its laws. provides the means of answering a large number of important practical problems, though it may not give a complete specific answer to any one of them Clinical- Patient-oriented res. Epidemiologic and behavioral, Outcomes & health services res.