Evidence Based Medicine

Fundamentals of Clinical Trials A clinical trial is a prospective study assessing the effect and value of intervention(s) vs. control in human subjects  Each clinical trial has a PRIMARY question (outcome)  There may be multiple SECONDARY outcomes  Trials are not powered to definitely answer most questions about secondary outcomes…interpret with caution 

Time (In Years) To Develop A New Drug (Average) Pre-Clinical Testing To Approval 1960s-1990s (US FDA) Pre-clinical

Clinical

Approval

1960s

3.6

2.8

2.4

1970s

4.6

4.4

2.1

1980s

4.7

5.7

2.8

1990s

4.7

6.6

1.9

Phase

Phase

Phase

Pitfalls Of The Current Model Of Drug Discovery & Development. - High and unaffordable costs of R&D and consequently of new drugs. - Too many products with identical pharmacological profile and mechanism – the milligram battle. - Low therapeutic rationale and advance for new drugs. - Many products especially biotech products developed through technology push rather than medical demand pull.

Can We Make Regulatory Submissions More Crisp And Meaningful No. of Words In Documents Pythagoras

Theorem

24

Archimedes

Principle

67

The

Ten Commandments

American

Declaration of Independence European Legislation on when and where one can smoke Average

IND Submission to FDA

179 300 24,942 800,000

At The Same Time Regulations in New Drugs Research Are Needed To: - To ensure safety and efficacy of New Drugs by an independent authority - To ensure that uniform and well-laid out standards apply to all products - To ensure that products are continuously monitored, post-marketing - To review safety and efficacy standards based on new knowledge - To recommend appropriate amendments to Drugs and Cosmetics Act

FDA REGULATIONS MOSTLY A REACTIVE RESPONSE

1906

History of FDA, USA, concerned only with purity.

1936

Elixir Sulfanilamide 10% solution in 70% Diethylene Glycol implicated in 105 deaths.

1938

Federal Food, Drug & Cosmetic Act passed concerned with safety, not efficacy – NDA to be approved.

1961

Thalidomide disaster in Europe.

1962

Kefauver-Harris Amendment passed regarding extensive safety and efficacy studies – IND mandatory.

1987

Format of IND changed.

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Criticisms & Negative Perceptions On Clinical Trials  Trial objectives skewed in favor of potential positive outcomes.  Cutting out tests likely to end in negative results.  Manipulation of Subject inclusion & exclusion criteria.  Outright fraud in selection of investigators with vested interests.  Suppression of publication of negative results.

To Eliminate Or Minimize These Negatives, Clinical Trials Need To Be Conducted Under Internationally Accepted Good Clinical Practice (GCP) Guidelines.  

GCP protects patients/subjects. GCP ensures that clinical trials produce accurate, credible data by: - defining standards - defining responsibilities

Good Clinical Practice 1962 1961

Drug Amendments Act

Thalidomide

1963 IND Procedure

ORIGINS 1977

1964

Proposed FDA Regulations covering obligations of Sponsors, Monitors and Clinical Investigators

Declaration of Helsinki

The Emergence Of ICH Guidelines ICH was evolved to negotiate common standards for the regulation of pharmaceutical products in Europe, Japan and U.S.A. According to its Mission Statement – ICH exists “to provide a forum for a constructive dialogue between the regulatory authorities and the pharma industry on the real and perceived differences in the technical requirements for product registration”.

ICH -International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use

(Objectives)

- Eliminate redundant & duplicative technical development. - Expedite global development. - Expedite availability of new medicines. - Maintaining safeguards on quality, safety & efficacy.

ICH Some key areas of interest : 





Safety reporting/Adverse Events (definitions and timings) New standards/templates (e.g., protocol, investigator’s brochure) Essential documents

Clinical Research An important Component Of The Regulatory System Has The Following Components

-Candidate Drug -Trial Sponsor - CRO/Monitor - Investigators & Trial Centers - Trial Subjects : Healthy Volunteers & Patients - Biostatisticians

The Investigator’s Obligations are spread over three phases. • Prior to Initiation of the trial • During The Trial 3) Post Trial

Prior To The Trials - The investigator should be excited about the study for its scientific merit rather than other considerations. - Should ensure that confidentiality should be maintained. - Should have sufficient time allocated to involve in the trials - Should be familiar with the product and well acquainted all pre-clinical data & IND dossier. - Ensure that there are adequate resources available & allocated. - Should discuss the Protocol & details of trials with Sponsor/Monitor. - Finalize local clearances, IEC, IRB etc as per the ICH guidelines, Informed Consent Forms .

During The Clinical Studies - Investigator should prepare a File containing all documents related to the Trial which should be kept in a secure area accessible to only him & his staff. - Patient identification codes & details should be preserved at least for 15 years and should be destroyed only with prior permission from the sponsor. - General medical Care should be provided to all subjects by the investigator or family physician. - Ensure strict adherence to randomization, unblinding etc as per the protocol. -- Safety & adverse reaction reports to be regularly obtained and action taken as per protocol to cause no or least damage to subjects. (ICH 4.11) -- Ensure proper completion/validation of the Case record Forms.. - Assess causality in terms of ‘not related, unlikely, possible, probable and most probable’, send reports and take corrective action.

INVESTIGATOR SOPs Objectives Ensuring that the investigator understands the responsibilities and obligations of the study. Planning & conducting the study as per the approved protocols and complying with ICH/GCP guidelines. Ensuring that the safety & welfare of the subjects are always the prime concern. Proper and accurate collection , Documentation & analysis of Data from the trials. Cooperate in inspections, monitoring and auditing of the study by third parties.

Investigators To Be Familiar With Documents Used By Ethics Committee. -GCP Guideline same -Investigator Brochure and safety Information. -Trial Protocol. -Consent Forms & Trial Information Sheets -Subject Recruitment Procedures. -Information on payment & remuneration to subjects. -Any Amendments To The Protocols Or SOPs.. -Any other document required by IEC/IRB.

See ICH Guidelines 3.1.2.

Nature Of Regulatory Inspections 2) Study related Inspections 3) Investigator Related Inspections -

Based on the pivotal nature of the study

Sponsor’s Difficulties in getting some Reports. -

Violation of trial protocol.

-

Work involved turns out to be outside competence of the investigator .

-

Results at variance with those of other investigators.

Inspection Reporting Systems • No lapse. • Requires corrective action for remediable lapses. • Warning letter if corrective action not taken or delayed, with copies to sponsor &reviewing IRB. •

Inviting for possible hearings.

•

Disqualification when the Investigator has deliberately violated the Agency’s regulatory standards or submitted false information.

Clinical Trials Deficiencies* (1999) Apart From Deliberate Fraud, Clinical Trials fail due to following categories of deficiencies Protocols

-

28%

Records & Documentation - 20% Adverse Drug Reaction Reporting - 15% Informed Consent

-

10%

Drug Accounting

-

10%

*Data From U.S.FDA.

FIDDES CASE- FRAUD AT ITS WORST From early 1990s Dr. Fiddes, President of a California based CRO had conducted over 200 Clinical Trials for 47 companies. Engaged in extensive fraudulent and falsified data, he was sentenced and jailed in Federal Prison for 15 months, a penalty of $ 800000 imposed in 1998 and was disqualified as a clinical investigator in 1999.

Glaxo Paxil Case-Emergence Of Transparency In Clinical Trials ✬ In the lawsuit against GSK, New York Attorney General Eliot Spitzer asserted that a novel fraud of suppression of information was committed in the promotion of Paxil for use as an anti-depressant. In August 2004, Glaxo started posting the full details of Clinical trials in their Website, creating a Clinical register and started inclusion of Safety & Efficacy data, off-label drug use issues etc in Medical Information Letters to Physicians... GSK also paid a fine of $ 2.5 million.

Profile of Regulatory Agencies: More applicable to Developing Countries - Need to balance the interests of the consumers as well as the industry. - Under-staffed and over-burdened: working on shoestring budgets. - No independent database to arrive at timely and scientific judgements. -Vulnerable to pressures from politicians and consumer activists. --No control Investigators.

on

recruitment

of

Clinical

Centers

&

- Dependency on ‘Experts’ who have little stake in the impact of their judgements on consumers or producers. Not equipped physically or technically to ensure compliance with GCP/ICH Guidelines

Fundamentals of Clinical Trials The study population must be defined in advance, with clear rationale and eligibility criteria A control group must always be used against which the new intervention can be compared Randomization is the most reliable way to assign participants to the treatment groups

Fundamentals of Clinical Trials A double blind design is the best way to avoid bias during collection of data If not possible, single blind and other methods should be utilized  Calculation of sample size should be sufficient to provide adequate power and levels of statistical significance 

Fundamentals of Clinical Trials Relevant BASELINE data should be acquired before initiation of intervention  All efforts should be made to collect accurate and consistent data  Need plan for assessment, analysis and reporting of adverse effects (AEs) and serious adverse events (SAEs) 

Evidence Based Medicine: Levels of Evidence Class I 1. Randomized double-blind, placebo-controlled trials 2. Meta-analyses of such RDBPC trials  Class II • Observational trials (case-control studies or concurrent control studies)  Class III • All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment.  Class IV: • Evidence from uncontrolled studies, case series, case reports, or expert opinion. 

Fundamentals of Clinical Trials FDA requires evidence of SAFETY and EFFICACY to consider approving medications for prescription use.  The process by which medications come to market goes through: preclinical development dose finding then safety trials exploratory efficacy/safety trials larger scale trials to determine the size and consistency of clinical effects, and develop more safety data 

Drug Development Process Discovery (2 - 10 years) 

Pre-clinical Testing Laboratory and animal testing  Phase 1- 20-80 healthy volunteers used to determine safety and dosage  Phase 2 - 100-300 patient volunteers used to look for efficacy (POC) and side effects  Phase 3 - 3,000-5,000 patient volunteers used to monitor adverse reactions to long-term use  FDA Review/Approval 

Diagnostic Test Studies  How

well does a test identify people with the disease? exclude people without the disease?  Compare test results on people with the disease with test results on people without the disease.  Need to know who has the disease.

Diagnostic Test Studies Two designs  Prospective or cohort design, or crosssectional design: take a sample of subject eligible for the test, test them all and get true diagnosis on them all.  Retrospective or case-control design: take a sample with true diagnosis established as positive and another sample of controls. We may have negative diagnosis established on controls and we may not. 

Who has the disease? True diagnosis.  We can never be absolutely sure that the ‘true’ diagnosis is correct.  We decide to accept one method as ‘true’: call this the gold standard or reference standard.  Often more invasive than the test, e.g. histopathology compared to ultrasound image.  It is always possible that the reference standard is wrong for some subjects.

Statistics of diagnostic test studies Sensitivity  Specificity  Receiver operating characteristic curve (ROC curve)  Likelihood ratio (LR) for positive test  Likelihood ratio (LR) for negative test  Odds ratio (OR)  Positive predictive value (PPV)  Negative predictive value (NPV) 

Statistics of diagnostic test studies  Example:

diabetic eye tests (cross-

sectional) test = direct opthalmoscopy reference standard = slit lamp stereoscopic biomicroscopy  Single sample of subjects all received reference standard test.

Statistics of diagnostic test studies  Sensitivity

= proportion of reference positive cases who are positive on the test = proportion of true cases that the test finds.  Specificity = proportion of reference negative cases who are negative on the test = proportion of true noncases that the test finds.

Example: eye disease in diabetics  45

reference standard positive cases of whom 40 were positive on the test, 275 reference standard negative noncases of whom 237 were negative on the test.  Sensitivity = 40/45 = 0.89 = 89%.  Specificity = 237/275 = 0.86 = 86%.

Statistics of diagnostic test studies  Positive

predictive value (PPV) = proportion of test positives who are reference positive.  Negative predictive value (NPV) = proportion of test negatives who are reference negative.

Example: eye disease in diabetics  78

test positives of whom 40 were positive on the reference standard, 242 test negatives of whom 237 were negative on the reference standard.  PPV = 40/78 = 51%.  NPV = 237/242 = 98%.

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Reading medical articles critically

Getting Ready Choose a few good peer-reviewed journal articles  Relevant to biomedical informatics  Interesting for you & audience  Important result or approach Send choices to instructor for feedback (2 weeks before your presentation)  Choose one article  Read critically  Take notes while reading  Reread even more critically  Skim related articles or web information

Creating the Content  Introduce

yourself  Why did you choose this paper?  How does it relate to your interests?  Summarize article (briefly!)  Provide context  Critique, question, react  Conclude

Summarize Article Assume audience read the paper  Do not assume audience understood it  Provide context When? Where? Why?  State authors’ take home messages  Focus on interesting/controversial issues 

Provide Context Research author and related work  Look up author’s webpage  Email author specific questions/clarifications  Compare & Contrast  Earlier work (follow citations)  Conflicting work (by others)  Alternative visions for same niche  Later work (follow citation index) 

Critique, Question, React Objectively Did the author(s) support their point? Was their support valid?  Subjectively How does it relate to your own experiences? Why did you find this paper interesting or important? What do you think the impact of this paper is? 

Conclude  Restate

author’s take-home message  State your own take-home message  Provide a personal perspective  Be provocative

Summary  Choose

a good article  Introduce yourself  Summarize article  Provide context  Critique, question, react  Conclude

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Types of medical studies.

The evidence pyramid

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Observational Studies 

– – –

–

Cohort

Question answered: “what will happen?” Prospective/forward e.g. Framingham study of cardiovascular disease: Started in 1948, 6000 citizens participated, followed for 20 years (study in 1970 by Gordon and Kannel) Possible uses:

  

Typical cohort study Outcome assessment (patient outcomes: economic, functional, satisfaction, QOL, ..) Historical Cohort studies/AKA Retrospective cohort: Relies on prospective records collected (If accurate) – still forward in time in the past

Cohort Studies

Cohort studies: marching towards outcomes

Lancet 2002; 359: 341-45

The defining characteristic of all cohort studies is that they track people forward in time from exposure to outcome. Data collection may be prospective or retrospective. Ex. Contraceptives and DVT.

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Observational Studies 

Case-Control – – – –

Retrospective Question answered: “What happened?” Matching needed for controls Might be difficult to differentiate from Case Series (Both are after the fact) 

Ask if the goal was to describe a phenomenon, if description is the goal  Case Series

Case Control Studies

Case-control Studies: research in reverse

Example: association between smoking and lung cancer. People with lung cancer are enrolled to form the case group, and people without lung cancer are identified as controls. Researchers then look back in time to ascertain each person's exposure status (smoking history), (retrospective design). Investigators compare the frequency of smoking exposure in the case group with that in the control group, and calculate a measure of association.

Observational Studies 

Case Series –

What are they? 

–

Author describes some interesting or intriguing observations that occurred to a small number of patients

Characteristics:   

 

The simplest design Descriptive Lead to hypotheses subsequently investigated by other types (Case-Control, Cross-Sectional or Cohort study) Generally over short period of time Generally no controls

Case Series & Case Reports

Both Cohort and Case-Control studies are called “Longitudinal Studies”

Notion of time

Observational Studies Case Series

Case-Control

Cohort

Longitudinal Studies

Cross Sectional

Experimental Studies 





AKA Clinical Trials (Involve humans) Easier to identify (usually explicitly stated in the abstract) Two main categories of clinical trials: 1. 2.

Controlled trials Uncontrolled trials

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Experimental Studies Controlled Trials 

Trials with independent concurrent controls – Double or single blind – Best is randomized assignment – Same point in time – These include: 

RCT:

– The epitome of all research designs – Provides the strongest evidence of concluding causation – Best insurance that results are due to the intervention



Nonrandomized trials: – Assignment not randomized – Opened to biases



Trials with self controls

– Subject to bias (Hawthorne effect) – Can do crossover study (with washout period in between)



Trials with external control

– Uses the results of another investigator’s research as a comparison – Historical controls can also be used: for disease with no cures yet

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Randomized Controlled Studies

The Double Blind Method

Experimental Studies 



Uncontrolled trials Investigator’s experience with the new drug or procedure is described but not formally compared with another one More likely to be used for interventions that are procedures rather than drug

Experimental Studies Controlled trials

Uncontrolled trials

Independent concurrent controls

Self controls

RCT

External controls

Non-randomized

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Systematic Reviews &Metaanalyses

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Study Pyramid Best

Worst

Classification of types of clinical research

Lancet 2002; 359: 57-61

Temporal direction of study designs

Lancet 2002; 359: 57-61

Clinical Trials  Advantages:

– RCT is the gold standard or reference  Disadvantages:

– Expensive – Long duration

Cohort Studies  Advantages:

– Design of choice for studying cause of a disease, course, risk factors  Disadvantages:

– Cannot be used to prove causation – Long studies can be costly – Vulnerable to patient attrition, migration

Case-Control Studies 

Advantages: – – –

Quickest Least expensive Good for rare diseases and diseases that take long time – Good for investigation of a preliminary hypothesis – Time factor research 

Disadvantages: – –

Large biases Difficult to find matching controls

Cross Sectional Studies  Advantages:

– Best for:  Determining

status quo of a disease  Prevalence of disease  Evaluation of diagnostic procedures

– Relatively quick and inexpensive  Disadvantages:

– Provide only a snapshot in time

Case Series  Advantages:

– Easy to write – May be extremely useful to investigators looking for causes of the observation  Disadvantages:

– Subject to many biases in patient selection – Should be viewed as hypothesis generating, not conclusive

EXPERIMENT 1 A

researcher assembles two groups of study participants with Lyme Disease. She administers the antibiotic doxycycline to one group and amoxicillin to the other. The researcher then measures which has more of a beneficial effect

EXPERIMENT 2 A

researcher identifies two groups of elderly immobilized patients in a nursing home. One group of patients is repositioned every two hours. The other group is repositioned every 1.5 hours. The researcher measures whether the incidence of bed sores is lower in the group repositioned every 1.5 hours than the group repositioned every 2 hours

EXPERIMENT 3 A

researcher develops a counseling program designed to increase medication compliance in AIDS patients. The researcher delivers the program to one group of patients but not another, then studies whether the group that underwent the counseling program adhered to their medication better than the group that did not

What do all three experiments have in common?

?

. 

In each case the researcher actively interfered with one group of study subjects and then compared the outcome with a similar group of subject that did not receive the same intervention. Experiments in which researchers interfere with their study subjects are known as clinical investigations. All examples above pertain to humans, but many clinical investigations are done using animal subjects, particularly for new or risky interventions

EXPERIMENT 1 

A researcher identifies a group of patients who were incorrectly diagnosed with Lyme Disease, then records whether the patients experienced adverse effects from the antibiotics they were prescribed for treatment of Lyme

EXPERIMENT 2 

A researcher identifies a group of elderly immobilized patients in a nursing home. The researcher follows the patients for 6 months and records the administration of any topical (skin) agent. At the end of the study period, the researcher conducts an analysis to determine whether certain topical regimens related to reduced incidence of bed sores

EXPERIMENT 3 

A researcher identifies a group of individuals with AIDS who have low medication compliance. The researcher administers a questionnaire to the patients to determine what factors relate to their poor compliance

What do all three experiments have in common?

?

.

.  In

each case the researcher does not actively manipulate or intervene with patients; rather, the researcher merely observes the effect of one or more factors on an outcome. It is easy to see why observational studies received their moniker

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Article Types

ORIGINAL RESEARCH Original Articles are scientific reports of the results of original clinical research. The text is limited to 2700 words, with an abstract, a maximum of 5 tables and figures (total), and up to 40 references.  Special Articles are scientific reports of original research in such areas as economic policy, ethics, law, and health care delivery. The text is limited to 2700 words, with an abstract, a maximum of 5 tables and figures (total), and up to 40 references 

CLINICAL CASES 

Brief Reports usually describe one to three patients or a single family. The text is limited to 2000 words, a maximum of 3 tables and figures (total), and up to 25 references. They begin with a brief summary of no more than 100 words.



Clinical Problem-Solving manuscripts consider the stepby-step process of clinical decision making. Information about a patient is presented to an expert clinician or clinicians in stages (indicated by boldface type in the manuscript) to simulate the way such information emerges in clinical practice. The clinician responds (in regular type) as new information is presented, sharing his or her reasoning with the reader. The text should not exceed 2500 words, and there should be no more than 20 references.

REVIEW ARTICLES  Review

articles are usually solicited by the editors. All review articles undergo the same peer-review and editorial process as original research reports.

Clinical Practice articles 

Are evidence-based reviews of topics relevant to practicing physicians, both primary care providers and specialists. Articles in this series should include the following sections: the clinical problem, strategies and evidence, areas of uncertainty, guidelines from professional societies, and the authors' conclusions and recommendations. The text is limited to 2500 words and a small number of figures and tables. These articles do not include an abstract.

Clinical Therapeutics articles 

Are evidence-based reviews of topics relevant to practicing physicians. The series focuses on clinically oriented information about specific forms of therapy, including drugs, devices, and procedures. Each article in the series begins with a clinical vignette describing a patient with a specified condition for whom the treatment under discussion has been recommended. This vignette is followed by a definition of the clinical problem, a description of the path physiology and how the therapy works, clinical evidence, clinical use (including costs), adverse effects, areas of uncertainty, guidelines, and recommendations. The text is limited to 2500 words. These articles do not include an abstract.

Current Concepts articles  Focus

on clinical topics, including those in specialty areas but of wide interest. The text is limited to 2400 words, with a maximum of 4 figures and tables (total), and up to 50 references. These articles do not include an abstract.

Drug Therapy articles  Detail

the pharmacology and use of specific drugs or classes of drugs, or the various drugs used to treat particular diseases. The text is limited to 4000 words, with a maximum of 6 figures and tables (total), and up to 120 references. These articles do not include an abstract.

Mechanisms of Disease articles  Discuss

the cellular and molecular mechanisms of diseases or categories of diseases. The text is limited to 3500 words, with a maximum of 6 figures and tables (total), and up to 100 references. These articles do not include an abstract.

Medical Progress articles 

Provide comprehensive, scholarly overviews of important clinical subjects, with the principal (but not exclusive) focus on developments during the past five years. Each article details how the perception of a disease, disease category, diagnostic approach, or therapeutic intervention has evolved in recent years. The text is limited to 3500 words, with a maximum of 6 tables and figures (total), and up to 100 references. These articles do not include an abstract.

OTHER SUBMISSIONS

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Editorials  Usually

provide commentary and analysis concerning an article in the issue of the Journal in which they appear. They may include 1 figure or table. They are nearly always solicited, although unsolicited editorials may occasionally be considered. Editorials are limited to 1000 words, with up to 15 references

Perspective articles  Cover

a wide variety of topics of current interest in health care, medicine, and the intersection between medicine and society. Perspective articles are limited to 1000 to 1200 words and usually include one figure. There is a maximum of 5 references

Sounding Board articles  Are

opinion essays. They are similar to editorials but are not tied to a particular article. They often present opinions on health policy issues and are normally unsolicited. The text is limited to 2000 words.

Clinical Implications of Basic Research articles  Discuss

single papers from preclinical journals. The purpose is to explain the findings and comment on their possible clinical applications in fewer than 750 words. There may be 1 figure and up to 4 references.

Special Reports  Are

miscellaneous articles of special interest to the medical community. They are limited to 2700 words.

Letters to the Editor  Provide

a forum for readers to comment about articles recently published in the Journal, and they are a place to publish concise articles, such as reports of novel cases