Clinical Document Architecture

The HL7 Clinical Document Architecture (CDA) is an XML-based markup standard intended to specify the encoding, structure and semantics of clinical documents for exchange. CDA is an ANSI-certified standard from Health Level Seven (HL7.org). Release 1.0 was published in November, 2000 and Release 2.0 was published with the HL7 2005 Normative Edition.
CDA specifies the syntax and supplies a framework for specifying the full semantics of a clinical document. It defines a clinical document as having the following six characteristics:

• Persistence
• Stewardship
• Potential for authentication
• Context
• Wholeness
• Human readability

A CDA can contain any type of clinical content. Typical CDA documents would be a Discharge Summary, Imaging Report, Admission & Physical, Pathology Report and so on. CDA uses XML, although it allows for a non-XML body (pdf, Word, jpg and so on) for simple implementations.
It was developed using the HL7 Development Framework (HDF) and it is based on the HL7 Reference Information Model (RIM) and the HL7 Version 3 Data Types.
The CDA specifies that the content of the document consists of a mandatory textual part (which ensures human interpretation of the document contents) and optional structured parts (for software processing). The structured part relies on coding systems (such as from SNOMED and LOINC) to represent concepts.
CDA Release 2 has been adopted as an ISO standard, ISO/HL7 27932:2009

Transport

The CDA standard doesn't specify how the documents should be transported. CDA documents can be transported using HL7 version 2 messages, HL7 version 3 messages, IHE protocols such as XDS, as well as by other mechanisms including: DICOM, MIME attachments to email, http or ftp.

Country specific notes

In the U.S. the CDA standard is probably best known as the basis for the Continuity of Care Document (CCD) specification, based on the data model as specified by ASTMs Continuity of Care Record. The U.S. Healthcare Information Technology Standards Panel has selected the CCD as one of its standard

FDA Fast Track Development Program

The FDA Fast Track Development Program is a designation of the United States Food and Drug Administration (FDA) that accelerates the approval of investigational new drugs undergoing clinical trials with the goal review time of 60 days. Such status is often given to agents that show promise in treating serious, life-threatening medical conditions for which no other drug either exists or works as well.
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need. The purpose is to get important new drugs to the patient earlier. Fast Track addresses a broad range of serious diseases. Determining whether a disease is serious is a matter of judgment, but generally is based on whether the drug will have an impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one.
Any drug being developed as a treatment or preventative measure for a disease that does not have a current therapy is labelled as an unmet need. If there are existing therapies, a fast track drug must show some advantage over available treatment, such as:

• Showing superior effectiveness
• Avoiding serious side effects of an available treatment
• Improving the diagnosis of a serious disease where early diagnosis results in an improved outcome
• Decreasing a clinically significant toxicity of an accepted treatment

A drug that receives Fast Track designation is eligible for some or all of the following:

• More frequent meetings with FDA to discuss the drug’s development plan and ensure collection of appropriate data needed to support drug approval
• More frequent written correspondence from FDA about such things as the design of the proposed clinical trials
• Eligibility for FDA Accelerated Approval, i.e., approval on an effect on a surrogate, or substitute endpoint reasonably likely to predict clinical benefit
• Rolling Review, which means that a drug company can submit completed sections of its New Drug Application (NDA) for review by FDA, rather than waiting until every section of the application is completed before the entire application can be reviewed. NDA review usually does not begin until the drug company has submitted the entire application to the FDA
• Dispute resolution if the drug company is not satisfied with an FDA decision not to grant Fast Track status.

In addition, most drugs that are eligible for Fast Track designation are likely to be considered appropriate to receive a Priority Review. Fast Track designation must be requested by the drug company. The request can be initiated at any time during the drug development process. FDA will review the request and make a decision within sixty days based on whether the drug fills an unmet medical need in a serious disease.
Once a drug receives Fast Track designation, early and frequent communication between the FDA and a drug company is encouraged throughout the entire drug development and review process. The frequency of communication assures that questions and issues are resolved quickly, often leading to earlier drug approval and access by patients.

Statistics

According to data on FDA website, Fast Track has generated the following workload from March 1998 to September 2011: Submitted 248 applications
Reviewed within 60 days:

• Granted - 152
• Denied - 87
• Currently pending - 2

Reviewed for longer than 60 days:

• Granted - 4
• Denied - 1
• Currently pending - 7

Abigail Alliance for Better Access to Developmental Drugs

The Abigail Alliance for Better Access to Developmental Drugs seeks broader availability of investigational drugs on behalf of terminally ill patients. It believes that patients have a right to decide, for themselves, whether to take an investigational drug that the FDA has approved for clinical trials. The FDA currently restricts access to those drugs to patients in clinical trials and patients who get a compassionate use exemption, which the Abigail Alliance believes is unduely burdensome.^[1]
The Abigail Alliance is best known for a legal case, which it lost, Abigail Alliance v. von Eschenbach, in which it was represented by the Washington Legal Foundation. On August 7, 2007, in an 8-2 ruling, the U.S. Court of Appeals for the District of Columbia Circuit reversed an earlier ruling in favor of the Alliance.^{[citation needed]}
In 2008, the Supreme Court of the United States declined to hear their appeal^[2] This decision left standing the appellate court decision that terminally ill patients have no legal right to demand "a potentially toxic drug with no proven therapeutic benefit."
The Abigail Alliance is a 501(c)(3) non-profit organization, incorporated in Virginia in 2001.

NEW DRUG APLLICATION

The New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the Food and Drug Administration (FDA) approve a new pharmaceutical for sale and marketing. The goals of the NDA are to provide enough information to permit FDA reviewers to establish the following:

• Is the drug safe and effective in its proposed use(s) when used as directed, and do the benefits of the drug outweigh the risks?

• Is the drug’s proposed labeling (package insert) appropriate, and what should it contain?

• Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity? 
  

  Before trials

  To legally test the drug on human subjects in the U.S., the maker must first obtain an Investigational New Drug (IND) designation from FDA. This application is based on pre-clinical data, typically from animal studies after P1, that shows the drug is safe enough to be tested in humans.
  Often the "new" drugs that are submitted for approval include new molecular entities or old medications that have been chemically modified to elicit differential pharmacological effects or reduced side-effects.
  

  Clinical trials

  The legal requirement for approval is "substantial" evidence of efficacy demonstrated through controlled clinical trials.^[1] This standard lies at the heart of the regulatory program for drugs. It means that the clinical experience of doctors, the opinion of experts, or testimonials from patients, even if they have experienced a miraculous recovery, have minimal weight in this process. Data for the submission must come from rigorous clinical trials.
  The trials are typically conducted in three phases:
  
• Phase 1: The drug is tested in a few healthy volunteers to determine if it is acutely toxic.
• Phase 2: Various doses of the drug are tried to determine how much to give to patients.
• Phase 3: The drug is typically tested in double-blind, placebo controlled trials to demonstrate that it works. Sponsors typically confer with FDA prior to starting these trials to determine what data is needed, since these trials often involve hundreds of patients and are very expensive.
• (Phase 4): These are post-approval trials that are sometimes a condition attached by the FDA to the approval.

The legal requirements for safety and efficacy have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs are toxic and technically not "safe" in the usual sense.
Many approved medications for serious illnesses (e.g., cancer) have severe and even life-threatening side effects. Even relatively safe and well understood OTC drugs such as aspirin can be dangerous if used incorrectly.

The actual application

The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information.^[2] The prescribing information is widely available on the web, from the FDA,^[3] drug manufacturers, and frequently inserted into drug packages. The main purpose of a drug label is to provide healthcare providers with adequate information and directions for the safe use of the drug.
The documentation required in an NDA is supposed to tell the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug formulation are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged. Currently, the decision process for FDA approval lacks transparency; however, efforts are underway to standardise the benefit-risk assessment of new medicines.^[4] Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the U.S.
Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess whether the NDA is "sufficiently complete to permit a substantive review". If the NDA is found to be insufficiently complete (and reasons for this can vary from a simple administrative mistake in the application to a requirement to reconduct much of the testing), then the FDA rejects the application with the issue of a Refuse to File letter which is sent to the applicant explaining where the application has failed to meet requirements.^[5]
Assuming that everything is found to be acceptable, the FDA will decide if the NDA will get a standard or accelerated review and communicate the acceptance of the application and their review choice in another communication known as the 74-day letter.^[6] A standard review implies an FDA decision within about 10 months while a priority review should complete within 6 months.^[7]
Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD format.^[8]

Requirements for similar products

Biologics, such as vaccines and many recombinant proteins used in medical treatments are generally approved by FDA via a Biologic License Application (BLA), rather than an NDA. The manufacture of biologics is considered to differ fundamentally from that of less complex chemicals, requiring a somewhat different approval process.
Generic drugs that have already been approved via an NDA submitted by another maker are approved via an Abbreviated New Drug Application (ANDA), which does not require all of the clinical trials normally required for a new drug in an NDA.^[9] Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law.^[10] However, a handful of biologic medicines, including biosynthetic insulin, growth hormone, glucagon, calcitonin, and hyaluronidase are grandfathered under governance of the Federal Food Drug and Cosmetics Act, which appears to be because these products were already approved when legislation aimed at regulating biotechnology medicines was later passed as part of the Public Health Services Act.
Biologic medicines governed under the Federal Food Drugs and Cosmetics Act has been an area of considerable confusion and dispute for the FDA, because under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, a "generic" need not be an exact duplicate of the brand-name original in order to be approved. In July 2003, the Sandoz generics unit of Novartis filed, and the FDA accepted, an ANDA for a "follow-on" version of Pfizer's brand-name human growth hormone (Genotropin) that Sandoz named Omnitrope using the 505(b)(2) pathway. The application was submitted following lengthy discussions with the FDA and contained preclinical, clinical, and comparability data, as well as literature references to the FDA's original decision on Pfizer's Genotropin. But on September 2, 2004, the FDA told Sandoz that the Agency was unable to reach a decision on whether to approve the company's application for Omnitrope. Frustrated with the FDA's failure to give them a decision on Omnitrope, Sandoz then sued the FDA in U.S. District Court in Washington, D.C., citing a statutory requirement that the FDA is required by law to act on drug applications within 180 days.
Medications intended for use in animals are submitted to a different center within FDA, the Center for Veterinary Medicine (CVM) in a New Animal Drug Application (NADA). These are also specifically evaluated for their use in food animals and their possible effect on the food from animals treated with the drug.

INVESTIGATIONAL NEW DRUG

The United States Food and Drug Administration's Investigational New Drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved. The FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is cleared, the candidate drug usually enters a Phase 1 clinical trial.

Criteria for application

An IND is required for a clinical study if it is intended to support a:

• New indication
• Change in the approved route of administration or dosage level
• Change in the approved patient population (e.g. pediatric) or a population at greater or increase of risk (elderly, HIV positive, immunocompromised)
• Significant change in the promotion of an approved drug

Application contents

The IND application must contain information in three broad areas:

• Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use).
• Chemistry and Manufacturing Information - Information pertaining to the chemical composition, manufacturing methods, stability, and controls used for manufacturing the drug substance and the drug product. The chemical stability and activity of the product must also have been tested. This information is assessed to ensure that the company can adequately produce and supply consistent and active batches of the drug.
• Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose the subjects to unnecessary risks. Information on the qualifications of clinical investigators—professionals (generally physicians) who oversee the administration of the experimental compound—to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations.

An IND must also include an Investigator's Brochure which is a document intended to educate the trial investigators of the significant facts about the trial drug they need to know to conduct their clinical trial with the least hazard to the subjects or patients who will be enrolled.

IND types

There are three IND types:

• An Investigator IND is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.
• Emergency Use IND allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND.
• Treatment IND is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.^[1]

Additional regulations

• Experimental drugs under an IND must be labeled, "Caution: New Drug--Limited by Federal (or United States) law to investigational use.

Noteworthy examples

The FDA closed its medical marijuana IND program (the Compassionate Investigational New Drug program) in 1991, facing an influx of AIDS patients seeking access to the drug. Seven patients continue to receive cannabis from the government under the program

PRE-CLINICAL DEVELOPEMENT

In drug development, pre-clinical development, also named preclinical studies and nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) can begin, and during which important feasibility, iterative testing and drug safety data is collected.
The main goals of pre-clinical studies are to determine a product's ultimate safety profile. Products may include new or iterated or like-kind medical devices, drugs, gene therapy solutions, etc

Types of preclinical research

Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics (what the body does to the drug) (PK), ADME, and toxicity testing through animal testing. This data allows researchers to allometrically estimate a safe starting dose of the drug for clinical trials in humans. Medical devices that do not have drug attached will not undergo these additional tests and may go directly to GLP testing for safety of the device and its components. Some medical devices will also undergo biocompatibility testing which helps to show whether a component of the device or all components are sustainable in a living model. Most pre-clinical studies must adhere to Good Laboratory Practices (GLP) in ICH Guidelines to be acceptable for submission to regulatory agencies such as the Food & Drug Administration in the United States.
Typically, both in vitro and in vivo tests will be performed. Studies of a drug's toxicity include which organs are targeted by that drug, as well as if there are any long-term carcinogenic effects or toxic effects on mammalian reproduction.

Animal testing

The information collected from these studies is vital so that safe human testing can begin. Typically, in drug development studies animal testing involves two species. The most commonly used models are murine and canine, although primate and porcine are also used.

Choice of species

The choice of species is based on which will give the best correlation to human trials. Differences in the gut, enzyme activity, circulatory system, or other considerations make certain models more appropriate based on the dosage form, site of activity, or noxious metabolites. For example, canines may not be good models for solid oral dosage forms because the characteristic carnivore intestine is underdeveloped compared to the omnivore's, and gastric emptying rates are increased. Also, rodents can not act as models for antibiotic drugs because the resulting alteration to their intestinal flora causes significant adverse effects. Depending on a drug's functional groups, it may be metabolized in similar or different ways between species, which will affect both efficacy and toxicology.
Medical device studies also use this basic premise. Most studies are performed in larger species such as dogs, pigs and sheep which allow for testing in a similar sized model as that of a human. In addition, some species are used for similarity in specific organs or organ system physiology (swine for dermatological and coronary stent studies; goats for mammary implant studies; dogs for gastric and cancer studies; etc.).

Ethical issues

Animal testing in the research-based pharmaceutical industry has been reduced in recent years both for ethical and cost reasons. However, most research will still involve animal based testing for the need of similarity in anatomy and physiology that is required for diverse product development.

No observable effect levels

Based on pre-clinical trials, No Observable Adverse Effect Levels (NOAEL) on drugs are established, which are used to determine initial phase 1 clinical trial dosage levels on a mass API per mass patient basis. Generally a 1/100 uncertainty factor or "safety margin" is included to account for interspecies (1/10) and inter-individual (1/10) differences.

DRUG DEVELOPEMENT

Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery. It includes pre-clinical research (microorganisms/animals) and clinical trials (on humans) and may include the step of obtaining regulatory approval to market the drug.

New chemical entity development

Regulation of therapeutic goods in the United States
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v t e

Broadly, the process of drug development can be divided into pre-clinical and clinical work.

Pre-clinical

New chemical entities (NCEs, also known as new molecular entities or NMEs) are compounds which emerge from the process of drug discovery. These will have promising activity against a particular biological target thought to be important in disease; however, little will be known about the safety, toxicity, pharmacokinetics and metabolism of this NCE in humans. It is the function of drug development to assess all of these parameters prior to human clinical trials. A further major objective of drug development is to make a recommendation of the dose and schedule to be used the first time an NCE is used in a human clinical trial ("first-in-man" [FIM] or First Human Dose [FHD]).
In addition, drug development is required to establish the physicochemical properties of the NCE: its chemical makeup, stability, solubility. The process by which the chemical is made will be optimized so that from being made at the bench on a milligram scale by a medicinal chemist, it can be manufactured on the kilogram and then on the ton scale. It will be further examined for its suitability to be made into capsules, tablets, aeresol, intramuscular injectable, subcuteneous injectable, or intravenous formulations. Together these processes are known in preclinical development as Chemistry, Manufacturing and Control (CMC).
Many aspects of drug development are focused on satisfying the regulatory requirements of drug licensing authorities. These generally constitute a number of tests designed to determine the major toxicities of a novel compound prior to first use in man. It is a legal requirement that an assessment of major organ toxicity be performed (effects on the heart and lungs, brain, kidney, liver and digestive system), as well as effects on other parts of the body that might be affected by the drug (e.g. the skin if the new drug is to be delivered through the skin). While, increasingly, these tests can be made using in vitro methods (e.g. with isolated cells), many tests can only be made by using experimental animals, since it is only in an intact organism that the complex interplay of metabolism and drug exposure on toxicity can be examined.
The information gathered from this pre-clinical testing, as well as information on CMC, and is submitted to regulatory authorities (in the US, to the FDA), as an Investigational New Drug application or IND. If the IND is approved, development moves to the clinical phase.

Clinical phase

Clinical trials involves three steps:

• Phase I trials, usually in healthy volunteers, determine safety and dosing.
• Phase II trials are used to get an initial reading of efficacy and further explore safety in small numbers of sick patients.
• Phase III trials are large, pivotal trials to determine safety and efficacy in sufficiently large numbers of patients.

The process of drug development does not stop once an NCE begins human clinical trials. In addition to the tests required to move a novel drug into the clinic for the first time it is also important to ensure that long-term or chronic toxicities are determined, as well as effects on systems not previously monitored (fertility, reproduction, immune system, etc.). The compound will also be tested for its capability to cause cancer (carcinogenicity testing).
If a compound emerges from these tests with an acceptable toxicity and safety profile, and it can further be demonstrated to have the desired effect in clinical trials, then it can be submitted for marketing approval in the various countries where it will be sold. In the US, this process is called a New Drug Application or NDA. Most NCEs, however, fail during drug development, either because they have some unacceptable toxicity, or because they simply do not work in clinical trials.

Cost

The full cost of bringing a new drug (i.e. a drug that is a new chemical entity) to market - from discovery through clinical trials to approval - is complex and controversial. One element of the complexity is that the much-publicized final numbers often do not include just the simple out-of-pocket expenses, but also include "capital costs", which are included to take into account the long time period (often at least ten years) during which the out-of-pocket costs are expended; additionally it is often not stated whether a given figure includes the capitalized cost or comprises only out-of-pocket expenses. Another element of complexity is that all estimates are based on confidential information owned by drug companies, released by them voluntarily. There is currently no way to validate these numbers. The numbers are controversial, as drug companies use them to justify the prices of their drugs and various advocates for lower drug prices have challenged them. The controversy is not only between "high" and "low" -- the numbers also vary greatly at the high end.
A study published by Steve Paul et al. in 2010 in Nature Reviews: Drug Discovery compares many of the studies, provides both capitalized and out-of-pocket costs for each, and lays out the assumptions each makes: see Supplemental Box 2.^[1] The authors offer their own estimate of the capitalized cost as being ~$1.8B, with out-of-pocket costs of ~$870M.
Studies published by diMasi et al. in 2003, report an average pre-tax, capitalized cost of approximately $800 million to bring one of the drugs from the study to market. Also, this $800 million dollar figure includes opportunity costs of $400 million.^[2] A study published in 2006 estimates that costs vary from around $500 million to $2 billion depending on the therapy or the developing firm.^[3] A study published in 2010 in the journal Health Economics, including an author from the US Federal Trade Commission, was critical of the methods used by diMasi et al. but came up with a higher estimate of ~$1.2 billion.^[4]

Success rate

Candidates for a new drug to treat a disease might theoretically include from 5,000 to 10,000 chemical compounds. On average about 250 of these will show sufficient promise for further evaluation using laboratory tests, mice and other test animals. Typically, about ten of these will qualify for tests on humans.^[5] A study conducted by the Tufts Center for the Study of Drug Development covering the 1980s and 1990s found that only 21.5 percent of drugs that start phase I trials are eventually approved for marketing.^[6] The high failure rates associated with pharmaceutical development are referred to as the "attrition rate" problem. Careful decision making during drug development is essential to avoid costly failures.^[7] In many cases, intelligent programme and clinical trial design can prevent false negative results. Well designed dose-finding studies and comparisons against both a placebo and a gold-standard treatment arm play a major role in achieving reliable data.^[8]

Novel initiatives to boost drug development

Novel initiaives include partnering between governmental organisations and industry. The worlds largest such initiative is the Innovative Medicines Initiative (IMI), and examples of major national initiatives are Top Institute Pharma in the Netherlands and Biopeople in Denmark.

Title 21 CFR Part 11

Title 21 CFR Part 11 of the Code of Federal Regulations deals with the United States Food and Drug Administration (FDA) guidelines on electronic records and electronic signatures (ERES). Part 11, as it is commonly called, defines the criteria under which electronic records and electronic signatures are considered to be trustworthy, reliable and equivalent to paper records (Title 21 CFR Part 11 Section 11.1 (a)).
Practically speaking, Part 11 requires drug makers, medical device manufacturers, biotech companies, biologics developers, CROs, and other FDA-regulated industries, with some specific exceptions, to implement controls, including audits, system validations, audit trails, electronic signatures, and documentation for software and systems involved in processing electronic data that are (a) required to be maintained by the FDA predicate rules or (b) used to demonstrate compliance to a predicate rule. A predicate rule is any requirement set forth in the Federal Food, Drug and Cosmetic Act, the Public Health Service Act, or any FDA regulation other than Part 11. [1]
The rule also applies to submissions made to the FDA in electronic format (e.g., a New Drug Application) but not to paper submissions by electronic methods (i.e., faxes). It specifically does not require the 21CFR11 requirement for record retention for tracebacks by food manufacturers. Most food manufacturers are not otherwise explicitly required to keep detailed records, but electronic documentation kept for HACCP and similar requirements must meet these requirements.
As of 2007, broad sections of the regulation have been challenged as excessive, and the FDA has stated in guidance that it will exercise enforcement discretion on many parts of the rule. This has led to confusion on exactly what is required, and the rule is being revised. (An update was posted on April 1, 2010 on the FDA Website). In practice, the requirements on access controls are the only part routinely enforced. The "predicate rules" which required the records to be kept in the first place are still in effect. If electronic records are illegible, inaccessible, or corrupted the manufacturers are still subject to those requirements.
If a regulated firm keeps "hard copies" of all required records, the paper documents can be considered to be the authoritative document for regulatory purposes and the computer system need not meet these requirements. Firms should be careful to make a claim that "hard copies" of required records are authoritative document. In order for the "hard copy" produced from its electronic source be considered as the authoritative document, the "hard copy" must (a) be a complete and accurate copy of its electronic source and (b) be used exclusively for regulated activities. The current technical architecture of computer systems increasingly makes the burden of proof for the complete and accurate copy requirement extremely high

Content

• Subpart A – General Provisions
  • Scope
  • Implementation
  • Definitions
• Subpart B – Electronic Records
  • Controls for closed systems
  • Controls for open systems
  • Signature manifestations
  • Signature/record linking
• Subpart C – Electronic Signatures
  • General requirements
  • Electronic signatures and controls
  • Controls for identification codes/passwords

History

• FDA Title 21 CFR Part 11:Electronic Records; Electronic Signatures; Final Rule (1997)

Various keynote speeches by FDA insiders early in the 21st century (in addition to high-profile audit findings focusing on computer system compliance) resulted in many companies scrambling to mount a defense against rule enforcement that they were procedurally and technologically unprepared for. Many vendors of software and instrumentation released Part 11 "compliant" updates, which proved to be either incomplete or insufficient to fully comply with the rule. Complaints about the wasting of critical resources, non-value added aspects, in addition to confusion within the drug, medical device, biotech/biologic and other industries about the true scope and enforcement aspects of Part 11 resulted in the FDA release of:

• FDA Guidance for Industry Part 11, Electronic Records: Electronic Signatures – Scope and Application (2003)

This document was intended to clarify how Part 11 should be implemented and would be enforced. But, as with all FDA guidances, it was not intended to convey the full force of law—rather, it expressed the FDA's "current thinking" on Part 11 compliance. Many within the industry, while pleased with the more limited scope defined in the guidance, complained that, in some areas, the 2003 guidance contradicted requirements in the 1997 Final Rule.

• Guidance for Industry Computerized Systems Used in Clinical Investigations

In May 2007, the FDA issued the final version of their guidance on computerized systems in clinical investigations. This guidance supersedes the guidance of the same name dated April 1999; and supplements the guidance for industry on Part 11, Electronic Records; Electronic Signatures — Scope and Application and the Agency’s international harmonization efforts when applying these guidances to source data generated at clinical study sites.
FDA had previously announced that a new Part 11 would be released late 2006. The Agency has since pushed that release date back. The FDA has not announced a revised time of release. John Murray, member of the Part 11 Working Group (the team at FDA developing the new Part 11), has publicly stated that the timetable for release is "flexible."

PATIENT REPORT OUTCOME

A patient-reported outcome or PRO is a questionnaire used in a clinical trial or a clinical setting, where the responses are collected directly from the patient.

 The term PRO should not be confused with patient-based outcomes. The latter implies that questionnaire covers issues of specific concern to the patient. However, patient-reported implies only that the patient provides the information. This information may, or may not, be of concern to the patient. The term PROs is synonymous with the increasing use of the term patient reported outcome measures (PROMs).

 Overview

PRO is an umbrella term that covers a whole range of potential types of measurement but is used specifically to refer to self-reports by the patient. PRO data may be collected via self-administered questionnaires completed by the patient themselves or via interviews. The latter will only qualify as a PRO where the interviewer is gaining the patient's views, not where the interviewer uses patient responses to make a professional assessment or judgment of the impact of the patient's condition. Thus, PROs are a means of gathering patient rather than clinical or other views on outcomes. This patients' perspective can play an important role in drug approval.

Characteristics

A well-designed PRO questionnaire should assess either a single underlying characteristic or, where it addresses multiple characteristics, should be a number of scales that each address a single characteristic. These measurement "characteristics" are termed constructs and the questionnaires used to collect them, termed instruments, measures, scales or tools.
A questionnaire that measures a single construct is described as unidimensional. Items (questions) in a unidimensional questionnaire can be added to provide a single scale score. However, it cannot be assumed that a questionnaire is unidimensional simply because the author intended it to be. This must be demonstrated empirically (for example, by confirmatory factor analysis or Rasch analysis). A questionnaire that measures multiple constructs is termed multi-dimensional. A multi-dimensional questionnaire is used to provide a profile of scores; that is, each scale is scored and reported separately. It is possible to create an overall (single summary) score from a multi-dimensional measure using factor analysis or preference-based methods but some may see this as akin to adding apples and oranges together.
Questionnaires may be generic (designed to be used in any disease population and cover a broad aspect of the construct measured) or condition-targeted (developed specifically to measure those aspects of outcome that are of importance for a people with a particular medical condition).
The most commonly used PRO questionnaires assess one of the following constructs:

• Symptoms (impairments) and other aspects of well-being
• Functioning (disability)
• Health status
• General health perceptions
• Quality of life (QoL)
• Health related quality of life (HRQoL)
• Reports and Ratings of health care.

Measures of symptoms may focus on a range of impairments or on a specific impairment such as depression or pain. Measures of functioning assess activities such as personal care, activities of daily living and locomotor activities. Health-related quality of life instruments are generally multi-dimensional questionnaires assessing a combination of aspects of impairments and/or disability and reflect a patient's health status. In contrast, QoL goes beyond impairment and disability by asking about the patient's ability to fulfill their needs and also about their emotional response to their restrictions.
A new generation of short and easy-to-use tools to monitor patient outcomes on a regular basis has been recently proposed.^[2] These tools are quick, effective, and easy to understand, as they allow patients to evaluate their health status and experience in a semi-structured way and accordingly aggregate input data, while automatically tracking their physio-emotional sensitivity. As part of the National Institute of Health's Roadmap Initiative, the Patient-Reported Outcomes Measurement Information System (PROMIS) uses modern advances in psychometrics such as Item Response Theory (IRT) and Computerized Adaptive Testing (CAT) to create highly reliable and validated measurement tools.

Validation and quality assessment

It is essential that a PRO instrument satisfy certain development, psychometric and scaling standards if it is to provide useful information. Specifically, measures should have a sound theoretical basis and should be relevant to the patient group with which they are to be used. They should also be reliable and valid (including responsive to underlying change) and the structure of the scale (whether it possesses a single or multiple domains) should have been thoroughly tested using appropriate methodology in order to justify the use of scale or summary scores.
These standards must be maintained throughout every target language population. In order to ensure that developmental standards are cosnistent in translated versions of a PRO instrument, the translated instrument undergoes a process known as Linguistic validation in which the preliminary translation is adapted to reflect cultural and linguistic differences between diverse target populations.

Examples

Many of the common generic PRO tools assess health-related quality of life or patient evaluations of health care. For example, the SF-36 Health Survey (SF-36 Health Survey), SF-12 Health Survey (SF-12 Health Survey), the Sickness Impact Profile, the Nottingham Health Profile, the Health Utilities Index, the Quality of Well-Being Scale, the EuroQol (EQ-5D), and the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey instruments are PRO instruments.
Condition-targeted tools may capture any of the constructs listed above, depending on the purpose for which they were designed. Examples include the Adult Asthma Quality of Life Questionnaire (AQLQ), the Kidney Disease Quality of Life Instrument, National Eye Institute Visual Functioning Questionnaire, Epilepsy Surgery Inventory, Migraine Specific Quality of Life (MSQOL), the Ankylosing Spondylititis Quality of Life questionnaire (ASQoL) and the Seattle Angina Questionnaire (SAQ), to name a few.

PROMs in the NHS

Since 1 April 2009 all providers of care funded by the National Health Service (NHS) in England have been required to provide Patient-Reported Outcome Measures (PROMs) in four elective surgical procedures: hip replacement, knee replacement, varicose vein surgery and hernia surgery.,.^[3][4] Patients are asked to complete a questionnaire before undergoing the surgical procedure; a follow-up questionnaire is then sent to the patient some weeks or months later.^[5] Patient participation is, however, not compulsory

REMOTE DATA ENTRY

Remote data capture is the process of automatic collection of scientific data. It is widely used in clinic trials,^[1] where it is referred to as electronic data capture. In physical sciences, automatic observation hardware in the field can be linked to an observer in a laboratory through a cellphone or other communication link.,^[2] for example in hydrology

CASE REPORT FORM(CRF)

A case report form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The Case Report Form is the tool used by the sponsor of the clinical trial to collect data from each participating site. All data on each patient participating in a clinical trial are held and/or documented in the CRF, including adverse events.
The sponsor of the clinical trial develops the CRF to collect the specific data they need in order to test their hypotheses or answer their research questions. The size of a CRF can range from a handwritten one-time 'snapshot' of a patient's physical condition to hundreds of pages of electronically captured data obtained over a period of weeks or months. (It can also include required check-up visits months after the patient's treatment has stopped.)
The sponsor is responsible for designing a CRF that accurately represents the protocol of the clinical trial, as well as managing its production, monitoring the data collection and auditing the content of the filled-in CRFs.
Case report forms contain data obtained during the patient's participation in the clinical trial. Before being sent to the sponsor, this data is usually de-identified (not traceable to the patient) by removing the patient's name, medical record number, etc., and giving the patient a unique study number. The supervising Institutional Review Board (IRB) oversees the release of any personally identifiable data to the sponsor.
From the sponsor's point of view, the main logistic goal of a clinical trial is to obtain accurate CRFs. However, because of human and machine error, the data entered in CRFs is rarely completely accurate or entirely readable. To combat these errors monitors are usually hired by the sponsor to audit the CRF to make sure the CRF contains the correct data.
When the study administrators or automated mechanisms process the CRFs that were sent to the sponsor by local researchers, they make a note of queries. Queries are non-sensible or questionable data that must be explained. Examples of data that would lead to a query: a male patient being on female birth control medication or having had an abortion, or a 15-year old participant having had hip replacement surgery. Each query has to be resolved by the individual attention of a member of each local research team, as well as an individual in the study administration. To ensure quality control, these queries are usually addressed and resolved before the CRF data is included by the sponsor in the final clinical study report. Depending on variables relating to the nature of the study, (e.g., the health of the study population), the effectiveness of the study administrators in resolving these queries can significantly impact the cost of studies.

eCRF

eCRF is an electronic case report form.

CLIICAL DATA ACQUISITION

Acquisition or collection of clinical trial data can be achieved through various methods that may include, but are not limited to, any of the following: paper or electronic medical records, paper forms completed at a site, interactive voice response systems, local electronic data capture systems, or central web based systems.
There is arguably no more important document than the instrument that is used to acquire the data from the clinical trial with the exception of the protocol, which specifies the conduct of that clinical trial. The quality of the data collected relies first and foremost on the quality of that instrument. No matter how much time and effort go into conducting the clinical trial, if the correct data points were not collected, a meaningful analysis may not be possible. It follows, therefore, that the design, development and quality assurance of such an instrument must be given the utmost attention.
The ICH guidelines on Good clinical practice (GCP) use the term ‘Case report form’ or ‘CRF’ to refer to these systems 1 . No matter what CRF is utilized, the quality and integrity of the data is of primary importance. The following recommendations are meant to assist in the design, development and quality assurance of the CRF such that the data collected will meet the highest standards.
For an extensive discussion regarding creation of CRFs and examples of actual data collection forms, see Data Collection Forms for Clinical Trials by Spilker 2 . The following is meant to highlight some of the most important points to consider during the design process.

Minimum standards

• Design the CRF to collect the data specified by the protocol.

• Document the process for CRF design, development, approval and version control.

• Make the CRF available at the clinical site prior to enrollment of a subject.

• Document training of clinical site personnel on the protocol, CRF completion instructions and data submittal procedures prior to enrollment of a subject.

Best practices

• Design the CRF along with protocol to assure collection of only the data that protocol specifies.

• Keep questions, prompts and instructions clear and concise.

• Design the CRF to follow the data flow from the perspective of the person completing it, taking into account the flow of study procedures and typical organization of data in a medical record.

• Avoid referential and redundant data points within the CRF whenever possible. If redundant data collection is used to assess data validity, the measurements should be obtained through independent means.

• Design the CRF with the primary safety and efficacy endpoints in mind as the main goal of data collection.

• Establish and maintain a library of standard forms.

• Make the CRF available for review at the clinical site prior to approval.

• Use NCR (no carbon required) paper or other means to assure exact replicas of paper collection tools.

ELECTRONIC DATA CAPTURE

An Electronic Data Capture (EDC) system is a computerized system designed for the collection of clinical data in electronic format for use mainly in human clinical trials. EDC replaces the traditional paper-based data collection methodology to streamline data collection and expedite the time to market for drugs and medical devices. EDC solutions are widely adopted by pharmaceutical companies and clinical research organizations (CRO).
Typically, EDC systems provide:

• a graphical user interface component for data entry
• a validation component to check user data
• a reporting tool for analysis of the collected data

EDC systems are used by life sciences organizations, broadly defined as the pharmaceutical, medical device and biotechnology industries in all aspects of clinical research,^[1] but are particularly beneficial for late-phase (phase III-IV) studies and pharmacovigilance and post-market safety surveillance, although some EDC system's such as SciAn Services edc^pro are specialized to include tools for phases I-II.
EDC can increase the data accuracy and decrease the time to collect data for studies of drugs and medical devices.^[2] The trade-off that many drug developers encounter with deploying an EDC system to support their drug development is that there is a relatively high start-up process, followed by significant benefits over the duration of the trial. As a result, for an EDC to be economical the saving over the life of the trial must be greater than the set-up costs. This is often aggravated by two conditions:

1. that initial design of the study in EDC does not facilitate the decrease in costs over the life of the study due to poor planning or inexperience with EDC deployment; and
2. initial set-up costs are higher than anticipated due to initial design of the study in EDC due to poor planning or experience with EDC deployment.

The net effect is to increase both the cost and risk to the study with insignificant benefits. However, with the maturation of today’s EDC solutions, such as Oracle Remote Data Capture (RDC) and OmniComm Systems’ TrialMaster EDC, Clinion^TM much of the earlier burdens for study design and set-up have been alleviated through technologies that allow for point-and-click, and drag-and-drop design modules. With little to no programming required, and reusability from global libraries and standardized forms such as CDISC’s CDASH, deploying EDC can now rival the paper processes in terms of study start-up time.^[3] As a result, even the earlier phase studies have begun to adopt EDC technology.

 HISTORY

EDC is often cited as having its origins in another class of software — Remote Data Entry (RDE) that surfaced in the life sciences market in the late 1980s and early 1990s. However its origins actually begin in the mid 1970s with a contract research organization known then as Institute for Biological Research and Development (IBRD). Dr. Richard Nichol and Joe Bollert contracted with Abbott Pharmaceuticals for the IBRD 'network' of Clinical Investigators to each have a computer and 'directly' enter clinical study data to the IBRD mainframe. IBRD then cleaned the data and provided reports to Abbott.
Clinical research data—patient data collected during the investigation of a new drug or medical device is collected by physicians, nurses, and research study coordinators in medical settings (offices, hospitals, universities) throughout the world. Historically, this information was collected on paper forms which were then sent to the research sponsor (e.g., a pharmaceutical company) for data entry into a database and subsequent statistical analysis environment. However, this process had a number of shortcomings:

• data are copied multiple times, which produces errors
• errors that are generated are not caught until weeks later
• visibility into the medical status of patients by sponsors is delayed

To address these and other concerns, RDE systems were invented so that physicians, nurses, and study coordinators could enter the data directly at the medical setting. By moving data entry out of the sponsor site and into the clinic or other facility, a number of benefits could be derived:

• data checks could be implemented during data entry, preventing some errors altogether and immediately prompting for resolution of other errors
• data could be transmitted nightly to sponsors, thereby improving the sponsor's ability to monitor the progress and status of the research study and its patients

These early RDE systems used "thick client" software—software installed locally on a laptop computer's hardware—to collect the patient data. The system could then use a modem connection over an analog phone line to periodically transmit the data back to the sponsor, and to collect questions from the sponsor that the medical staff would need to answer.
Though effective, RDE brought with it several shortcomings as well. The most significant shortcoming was that hardware (e.g., a laptop computer) needed to be deployed, installed, and supported at every investigational (medical) site. In addition to being expensive for sponsors and complicated for medical staff, this model resulted in a proliferation of laptop computers at many investigational sites that participated in more than one research study simultaneously. Usability and space constraints led to a lot of dissatisfaction among medical practitioners. With the rise of the Internet in the mid 1990s, the obvious solution to some of these issues was the adoption of web-based software that could be accessed using existing computers at the investigational sites. EDC represents this new class of software.

  Current landscape

The EDC landscape has continued to evolve from its evolution from RDE in the late 1990s, leveraging the latest in internet-based technologies. Today the market consists of a variety of new and established software providers. Many of these providers offer specialized solutions targeting certain customer profiles or study phases. In addition to pure software companies; some pharmaceutical, biotech and contract research organizations have developed their own EDC systems (ex: Cisys LifeSciences Sequence EDC Platform, e-SOCDAT, edc^pro, Clinion).This practice, however, was more popular back in the mid to late 1990s, With the evolution of the EDC marketplace, developing customized solutions has given way to more commercial-off-the-shelf (COTS) solutions as technology has improved over the years.

The future of EDC

As EDC software continues to mature, vendors are including capabilities that would have previously been developed and sold as separate software solutions: clinical data management systems (CDMS), clinical trial management systems (CTMS), business intelligence and reporting, and others. Efforts are being made to integrate payment execution tied to EDC data as well (such as Greenphire's eClinicalGPS product). This convergence is expected to continue until electronic patient medical records become more pervasive within the broader healthcare ecosystem—at which point the ideal solution would be to extract patient data directly from the electronic medical records as opposed to collecting the data in a separate data collection instrument. Standards such as CDISC and HL7 are already enabling this type of interoperability to be explored.

CLINICAL QUALITY MANAGEMENT SYSTEM

A Clinical Quality Management System (CQMS) allows an entire practice staff to take part in increasing the quality of care delivered to their patients. Acting as a real-time dashboard on care, a CQMS lets a care team know the status of each of their patients regarding needed preventive, screening and chronic disease management services based on practice-specified care guidelines. With tools to reach patients at the point-of-care and those not scheduled for a visit, a CQMS ensures the entire patient population is managed effectively and efficiently.

clinical data management system

A clinical data management system or CDMS is a tool used in clinical research to manage the data of a clinical trial. The clinical trial data gathered at the investigator site in the case report form are stored in the CDMS. To reduce the possibility of errors due to human entry, the systems employ various means to verify the data. Clinical data management can be a self-contained system or part of the functionality of a CTMS. A CTMS with clinical data management functionality can help with the validation of clinical data as well as the help the site employ the data for other important activities like building patient registries and assist in patient recruitment efforts.
CLASSIFICATION
The CDMS can be broadly divided into paper-based and electronic data capturing systems.

Paper-based systems

Case report forms are manually filled at site and mailed to the company for which trial is being performed. The data on forms is transferred to the CDMS tool through data entry.The most popular method being double data entry where two different data entry operators enter the data in the system independently and both the entries are compared by the system. In case the entry of a value conflicts, system alerts and a verification can be done manually. Another method is Single Data Entry.
The data in CDMS are then transferred for the data validation. Also, in these systems during validation the data clarification from sites are done through paper forms, which are printed with the problem description and sent to the investigator site and the site responds by answering on forms and mailing them back.

Electronic data capturing systems

In such CDMS the investigators directly uploads the data on CDMS and the data can then be viewed by the data validation staff. Once the data are uploaded by site, data validation team can send the electronic alerts to sites if there are any problems.
Such systems eliminate paper usage in clinical trial validation of data. Case report forms are manually filled at site and mailed to the company for which trial is being performed. The data on forms is transferred to the CDMS tool through data entry.The most popular method being double data entry where two different data entry operators enter the data in the system independently and both the entries are compared by the system. In case the entry of a value conflicts, system alerts and a verification can be done manually. Another method is Single Data Entry.
The data in CDMS are then transferred for the data validation. Also, in these systems during validation the data clarification from sites are done through paper forms, which are printed with the problem description and sent to the investigator site and the site responds by answering on forms and mailing them back.

Clinical data management

Once data have been screened for typographical errors, the data can be validated to check for logical errors. An example is a check of the subject's date of birth to ensure that they are within the inclusion criteria for the study. These errors are raised for review to determine if there are errors in the data or if clarifications from the investigator are required.
Another function that the CDMS can perform is the coding of data. Currently, the coding is generally centered around two areas — adverse event terms and medication names. With the variance on the number of references that can be made for adverse event terms or medication names, standard dictionaries of these terms can be loaded into the CDMS. The data items containing the adverse event terms or medication names can be linked to one of these dictionaries. The system can check the data in the CDMS and compare them to the dictionaries. Items that do not match can be flagged for further checking. Some systems allow for the storage of synonyms to allow the system to match common abbreviations and map them to the correct term. As an example, ASA (acetylsalicylic acid) could be mapped to aspirin, a common notation. Popular adverse event dictionaries are MedDRA and WHOART and popular Medication dictionaries are COSTART and WHO Drug Dictionary.
At the end of the clinical trial the data set in the CDMS is extracted and provided to statisticians for further analysis. The analysed data are compiled into clinical study report and sent to the regulatory authorities for approval.
Most of the drug manufacturing companies are using Web-based systems for capturing, managing and reporting clinical data. This not only helps them in faster and more efficient data capture, but also speeds up the process of drug development. Perceptive Informatics, Medidata RAVE and Forte Research Systems' OnCore eClinical are examples of Web-based data capture systems. In such systems, studies can be set up for each drug trial. In-built edit checks help in removing erroneous data. The system can also be connected to other external systems. For example, RAVE can be connected to an IVRS (Interactive Voice Response System) facility to capture data through direct telephonic interviews of patients.
 

clinical trial-economics: sponsor; investigator;subjects; participating in a clinical trial; locating trials; steps for volunteers; IT; controversy

Sponsor

The cost of a study depends on many factors, especially the number of sites conducting the study, the number of patients required, and whether the study treatment is already approved for medical use. Clinical trials follow a standardized process.
The costs to a pharmaceutical company of administering a Phase 3 or 4 clinical trial may include, among others:

• manufacturing the drug(s)/device(s) tested
• staff salaries for the designers and administrators of the trial
• payments to the contract research organization, the site management organization (if used) and any outside consultants
• payments to local researchers (and their staffs) for their time and effort in recruiting patients and collecting data for the sponsor
• study materials and shipping
• communication with the local researchers, including on-site monitoring by the CRO before and (in some cases) multiple times during the study
• one or more investigator training meetings
• costs incurred by the local researchers, such as pharmacy fees, IRB fees and postage
• any payments to patients enrolled in the trial (all payments are strictly overseen by the IRBs to ensure the patients do not feel coerced to take part in the trial by overly attractive payments)

These costs are incurred over several years.
In the US, sponsors may receive a 50% tax credit for certain clinical trials.^[36]
National health agencies, such as the US National Institutes of Health, offer grants to investigators who design clinical trials that attempt to answer research questions of interest to the agency. In these cases, the investigator who writes the grant and administers the study acts as the sponsor, and coordinates data collection from any other sites. These other sites may or may not be paid for participating in the study, depending on the amount of the grant and the amount of effort expected from them.
Clinical trials are traditionally expensive and difficult to undertake. Using internet resources can, in some cases, reduce the economic burden.^[37]

Investigators

Many clinical trials do not involve any money. However, when the sponsor is a private company or a national health agency, investigators are almost always paid to participate. These amounts can be small, just covering a partial salary for research assistants and the cost of any supplies (usually the case with national health agency studies), or be substantial and include 'overhead' that allows the investigator to pay the research staff during times between clinical trials.

Subjects

Participants in Phase 1 drug trials do not gain any direct benefit from taking part. They are generally paid an inconvenience allowance because they give up their time (sometimes away from their homes); the amounts paid are regulated and are not related to the level of risk involved. In most other trials, subjects are not paid to ensure their motivation for participating is the hope of getting better or contributing to medical knowledge, without their judgment being skewed by financial considerations. However, they are often given small payments for study-related expenses such as travel or as compensation for their time in providing follow-up information about their health after they are discharged from medical care.

Participation as Labour

It has been suggested that clinical trial participants be considered to be performing ‘experimental' or 'clinical labour’. Re-classifying clinical trials as labour is supported by the fact that information gained from clinical trials contributes to biomedical knowledge,^[38] and thus increases the profits of pharmaceutical companies. The labour performed by those participants in clinical trials includes the provision of tissue samples and information, the performance of other tasks, such as adhering to a special diet, or (in the case of Phase I trials particularly) exposing themselves to risk.^[39] The participants in exchange are offered potential access to medical treatment. For some, this may be a treatment with the potential to succeed where other treatments have failed. For other individuals, particularly those situated in countries such as China or India, they may be given access to healthcare which they otherwise would be unable to afford, for the duration of the trial.^[40][41][42] Thus, the exchange which exists may serve to classify clinical trials as a form of labour.

Participating in a clinical trial

Newspaper advertisements seeking patients and healthy volunteers to participate in clinical trials

Phase 0 and Phase 1 drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. The diversity observed in society, by consensus, should be reflected in clinical trials through the appropriate inclusion of ethnic minority populations.^[43]Patient recruitment plays a significant role in the activities and responsibilities of sites conducting clinical trials.

Locating trials

Depending on the kind of participants required, sponsors of clinical trials use various recruitment strategies, including patient databases, newspaper and radio advertisements, flyers, posters in places the patients might go (such as doctor's offices), and personal recruitment of patients by investigators.
Volunteers with specific conditions or diseases have additional online resources to help them locate clinical trials. For example, people with Parkinson's disease can use PDtrials to find up-to-date information on Parkinson's disease trials currently enrolling participants in the US and Canada, and search for specific Parkinson's clinical trials using criteria such as location, trial type, and symptom.^[44] Other disease-specific services exist for volunteers to find trials related to their condition.^[45] Volunteers may search directly on ClinicalTrials.gov to locate trials using a registry run by the U.S. National Institutes of Health and National Library of Medicine.
However, many clinical trials will not accept participants who contact them directly to volunteer, as it is believed this may bias the characteristics of the population being studied. Such trials typically recruit via networks of medical professionals who ask their individual patients to consider enrollment.^{[citation needed]}

Steps for volunteers

Before participating in a clinical trial, interested volunteers should speak with their doctors, family members, and others who have participated in trials in the past. After locating a trial, volunteers will often have the opportunity to speak or e-mail the clinical trial coordinator for more information and to answer any questions. After receiving consent from their doctors, volunteers then arrange an appointment for a screening visit with the trial coordinator.^[46]
All volunteers being considered for a trial are required to undertake a medical screening. Requirements differ for different trials, but typically volunteers will have the following tests in a medical laboratory:^[47]

• Measurement of the electrical activity of the heart (ECG)
• Measurement of blood pressure, heart rate and temperature
• Blood sampling
• Urine sampling
• Weight and height measurement
• Drugs abuse testing
• Pregnancy testing (females only)

Information technology

The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems are often used by research sponsors or CROs to help plan and manage the operational aspects of a clinical trial, particularly with respect to investigational sites. Web-based electronic data capture (EDC) and clinical data management systems are used in a majority of clinical trials^[48] to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response systems are used by sites to register the enrollment of patients using a phone and to allocate patients to a particular treatment arm (although phones are being increasingly replaced with web-based (IWRS) tools which are sometimes part of the EDC system). Patient-reported outcome measures are being increasingly collected using hand-held, sometimes wireless ePRO (or eDiary) devices. Statistical software is used to analyze the collected data and prepare them for regulatory submission. Access to many of these applications are increasingly aggregated in web-based clinical trial portals. In 2011, the FDA approved a Phase 1 trial that used telemonitoring, also known as remote patient monitoring, to collect biometric data in patients' homes and transmit it electronically to the trial database. This technology provides many more data points and is far more convenient for patients, because they have fewer visits to trial sites.

Controversy

In 2001, the editors of 12 major journals issued a joint editorial, published in each journal, on the control over clinical trials exerted by sponsors, particularly targeting the use of contracts which allow sponsors to review the studies prior to publication and withhold publication. They strengthened editorial restrictions to counter the effect. The editorial noted that contract research organizations had, by 2000, received 60% of the grants from pharmaceutical companies in the US. Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results.^[49]
Seeding trials are particularly controversial.^[50]