Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety (or more specifically, information about adverse drug reactions and adverse effects of other treatments) and efficacy data to be collected for health interventions (e.g., drugs, diagnostics, devices, therapy protocols). These trials can take place only after satisfactory information has been gathered on the quality of the non-clinical safety, and Health Authority/Ethics Committee approval is granted in the country where the trial is taking place.

Depending on the type of product and the stage of its development, investigators enroll healthy volunteers and/or patients into small pilot studies initially, followed by larger scale studies in patients that often compare the new product with the currently prescribed treatment. As positive safety and efficacy data are gathered, the number of patients is typically increased. Clinical trials can vary in size from a single center in one country to multicenter trials in multiple countries.

Due to the sizable cost a full series of clinical trials may incur, the burden of paying for all the necessary people and services is usually borne by the sponsor who may be a governmental organization, a pharmaceutical, or biotechnology company. Since the diversity of roles may exceed resources of the sponsor, often a clinical trial is managed by an outsourced partner such as a contract research organization or a clinical trials unit in the academic sector.

Overview[link]

Clinical trials often involve patients with specific health conditions who then benefit from receiving otherwise unavailable treatments. In early phases, participants are healthy volunteers who receive financial incentives for their inconvenience. During dosing periods, study subjects typically remain on site at the unit for durations of anything from 1 to 30 nights, occasionally longer, although this is not always required.

In planning a clinical trial, the sponsor or investigator first identifies the medication or device to be tested. Usually, one or more pilot experiments are conducted to gain insights for design of the clinical trial to follow. In medical jargon, effectiveness is how well a treatment works in practice and efficacy is how well it works in a clinical trial. In the U.S., the elderly comprise only 14% of the population but they consume over one-third of drugs.^[1] Despite this, they are often excluded from trials because their more frequent health issues and drug use produce unreliable data. Women, children, and people with unrelated medical conditions are also frequently excluded.^[2]

In coordination with a panel of expert investigators (usually physicians well known for their publications and clinical experience), the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo), and what kind of patients might benefit from the medication or device. If the sponsor cannot obtain enough patients with this specific disease or condition at one location, then investigators at other locations who can obtain the same kind of patients to receive the treatment would be recruited into the study.

During the clinical trial, the investigators: recruit patients with the predetermined characteristics, administer the treatment(s), and collect data on the patients' health for a defined time period. These patients are volunteers and they are not paid for participating in clinical trials. These data include measurements like vital signs, concentration of the study drug in the blood, and whether the patient's health improves or not. The researchers send the data to the trial sponsor who then analyzes the pooled data using statistical tests.

Some examples of what a clinical trial may be designed to do:

• Assess the safety and effectiveness of a new medication or device on a specific kind of patient (e.g., patients who have been diagnosed with Alzheimer's disease)
• Assess the safety and effectiveness of a different dose of a medication than is commonly used (e.g., 10 mg dose instead of 5 mg dose)
• Assess the safety and effectiveness of an already marketed medication or device for a new indication, i.e. a disease for which the drug is not specifically approved
• Assess whether the new medication or device is more effective for the patient's condition than the already used, standard medication or device ("the gold standard" or "standard therapy")
• Compare the effectiveness in patients with a specific disease of two or more already approved or common interventions for that disease (e.g., Device A vs. Device B, Therapy A vs. Therapy B)

Note that while most clinical trials compare two medications or devices, some trials compare three or four medications, doses of medications, or devices against each other.

Except for very small trials limited to a single location, the clinical trial design and objectives are written into a document called a clinical trial protocol. The protocol is the 'operating manual' for the clinical trial and ensures that researchers in different locations all perform the trial in the same way on patients with the same characteristics. (This uniformity is designed to allow the data to be pooled.) A protocol is always used in multicenter trials.

Because the clinical trial is designed to test hypotheses and rigorously monitor and assess what happens, clinical trials can be seen as the application of the scientific method, and specifically the experimental step, to understanding human or animal biology.

The most commonly performed clinical trials evaluate new drugs, medical devices (like a new catheter), biologics, psychological therapies, or other interventions. Clinical trials may be required before the national regulatory authority^[3] approves marketing of the drug or device, or a new dose of the drug, for use on patients.

History[link]

The history of clinical trials before 1750 is brief.^[4][5]

Edward Jenner vaccinating James Phipps, a boy of eight, on 14 May 1796.

The concepts behind clinical trials, however, are ancient. The Book of Daniel chapter 1, verses 12 through 15, for instance, describes a planned experiment with both baseline and follow-up observations of two groups who either partook of, or did not partake of, "the King's meat" over a trial period of ten days. Persian physician and philosopher, Avicenna, gave such inquiries a more formal structure.^[6] In The Canon of Medicine in 1025 AD, he laid down rules for the experimental use and testing of drugs and wrote a precise guide for practical experimentation in the process of discovering and proving the effectiveness of medical drugs and substances.^[7] He laid out the following rules and principles for testing the effectiveness of new drugs and medications:^{[8][9][verification needed]}

1. The drug must be free from any extraneous accidental quality.
2. It must be used on a simple, not a composite, disease.
3. The drug must be tested with two contrary types of diseases, because sometimes a drug cures one disease by its essential qualities and another by its accidental ones.
4. The quality of the drug must correspond to the strength of the disease. For example, there are some drugs whose heat is less than the coldness of certain diseases, so that they would have no effect on them.
5. The time of action must be observed, so that essence and accident are not confused.
6. The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect.
7. The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man.

One of the most famous clinical trials was James Lind's demonstration in 1747 that citrus fruits cure scurvy.^[10] He compared the effects of various different acidic substances, ranging from vinegar to cider, on groups of afflicted sailors, and found that the group who were given oranges and lemons had largely recovered from scurvy after 6 days.

Frederick Akbar Mahomed (d. 1884), who worked at Guy's Hospital in London,^[11] made substantial contributions to the process of clinical trials during his detailed clinical studies, where "he separated chronic nephritis with secondary hypertension from what we now term essential hypertension." He also founded "the Collective Investigation Record for the British Medical Association; this organization collected data from physicians practicing outside the hospital setting and was the precursor of modern collaborative clinical trials and t123."^[12]

Types[link]

One way of classifying clinical trials is by the way the researchers behave.

• In an observational study, the investigators observe the subjects and measure their outcomes. The researchers do not actively manage the study. An example is the Nurses' Health Study.
• In an interventional study, the investigators give the research subjects a particular medicine or other intervention. Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. Then the researchers measure how the subjects' health changes.

Another way of classifying trials is by their purpose. The U.S. National Institutes of Health (NIH) organizes trials into five (5) different types:^[13]

• Prevention trials: look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.
• Screening trials: test the best way to detect certain diseases or health conditions.
• Diagnostic trials: conducted to find better tests or procedures for diagnosing a particular disease or condition.
• Treatment trials: test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
• Quality of life trials: explore ways to improve comfort and the quality of life for individuals with a chronic illness (a.k.a. Supportive Care trials).
• Compassionate use trials or expanded access: provide partially tested, unapproved therapeutics prior to a small number of patients that have no other realistic options. Usually, this involves a disease for which no effective therapy exists, or a patient that has already attempted and failed all other standard treatments and whose health is so poor that he does not qualify for participation in randomized clinical trials.^[14] Usually, case by case approval must be granted by both the FDA and the pharmaceutical company for such exceptions.

Design[link]

A fundamental distinction in evidence-based medicine is between observational studies and randomized controlled trials. Types of observational studies in epidemiology such as the cohort study and the case-control study provide less compelling evidence than the randomized controlled trial. In observational studies, the investigators only observe associations (correlations) between the treatments experienced by participants and their health status or diseases.

A randomized controlled trial is the study design that can provide the most compelling evidence that the study treatment causes the expected effect on human health.

Currently, some Phase 2 and most Phase 3 drug trials are designed as randomized, double blind, and placebo-controlled.

• Randomized: Each study subject is randomly assigned to receive either the study treatment or a placebo.
• Blind: The subjects involved in the study do not know which study treatment they receive. If the study is double-blind, the researchers also do not know which treatment is being given to any given subject. This 'blinding' is to prevent biases, since if a physician knew which patient was getting the study treatment and which patient was getting the placebo, he/she might be tempted to give the (presumably helpful) study drug to a patient who could more easily benefit from it. In addition, a physician might give extra care to only the patients who receive the placebos to compensate for their ineffectiveness. A form of double-blind study called a "double-dummy" design allows additional insurance against bias or placebo effect. In this kind of study, all patients are given both placebo and active doses in alternating periods of time during the study.
• Placebo-controlled: The use of a placebo (fake treatment) allows the researchers to isolate the effect of the study treatment.

Although the term "clinical trials" is most commonly associated with the large, randomized studies typical of Phase 3, many clinical trials are small. They may be "sponsored" by single physicians or a small group of physicians, and are designed to test simple questions. In the field of rare diseases sometimes the number of patients might be the limiting factor for a clinical trial. Other clinical trials require large numbers of participants (who may be followed over long periods of time), and the trial sponsor is a private company, a government health agency, or an academic research body such as a university.

Active comparator studies[link]

Of note, during the last ten years or so it has become a common practice to conduct "active comparator" studies (also known as "active control" trials). In other words, when a treatment exists that is clearly better than doing nothing for the subject (i.e. giving them the placebo), the alternate treatment would be a standard-of-care therapy. The study would compare the 'test' treatment to standard-of-care therapy.

A growing trend in the pharmacology field involves the use of third-party contractors to obtain the required comparator compounds. Such third parties provide expertise in the logistics of obtaining, storing, and shipping the comparators. As an advantage to the manufacturer of the comparator compounds, a well-established comparator sourcing agency can alleviate the problem of parallel importing (importing a patented compound for sale in a country outside the patenting agency's sphere of influence).^{[citation needed]}

Clinical trial protocol[link]

A clinical trial protocol is a document used to gain confirmation of the trial design by a panel of experts and adherence by all study investigators, even if conducted in various countries.

The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations, and organization of the planned trial. Details of the trial are also provided in other documents referenced in the protocol such as an Investigator's Brochure.

The protocol contains a precise study plan for executing the clinical trial, not only to assure safety and health of the trial subjects, but also to provide an exact template for trial conduct by investigators at multiple locations (in a "multicenter" trial) to perform the study in exactly the same way. This harmonization allows data to be combined collectively as though all investigators (referred to as "sites") were working closely together. The protocol also gives the study administrators (often a contract research organization or CRO) as well as the site team of physicians, nurses and clinic administrators a common reference document for site responsibilities during the trial.

The format and content of clinical trial protocols sponsored by pharmaceutical, biotechnology or medical device companies in the United States, European Union, or Japan has been standardized to follow Good Clinical Practice guidance^[15] issued by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).^[16] Regulatory authorities in Canada and Australia also follow ICH guidelines. Some journals, e.g. Trials, encourage trialists to publish their protocols in the journal.

Design features[link]

Informed consent[link]

An essential component of initiating a clinical trial is to recruit study subjects following procedures using a signed document called "informed consent".^[17] Generally, children participating in clinical trial cannot autonomously provide informed consent, but depending on their age and other factors may be required to provide informed assent.

Informed consent is a legally defined process of a person being told about key facts involved in a clinical trial before deciding whether or not to participate. To fully describe participation to a candidate subject, the doctors and nurses involved in the trial explain the details of the study using terms the person will understand. Foreign language translation is provided if the participant's native language is not the same as the study protocol.

The research team provides an informed consent document that includes trial details, such as its purpose, duration, required procedures, risks, potential benefits and key contacts. The participant then decides whether or not to sign the document in agreement. Informed consent is not an immutable contract, as the participant can withdraw at any time without penalty.

Statistical power[link]

The number of patients enrolled in a study has a large bearing on the ability of the study to reliably detect the size of the effect of the study intervention. This is described as the "power" of the trial. The larger the sample size or number of participants in the trial, the greater the statistical power.

However, in designing a clinical trial, this consideration must be balanced with the fact that more patients make for a more expensive trial. The power of a trial is not a single, unique value; it estimates the ability of a trial to detect a difference of a particular size (or larger) between the treated (tested drug/device) and control (placebo or standard treatment) groups. By example, a trial of a lipid-lowering drug versus placebo with 100 patients in each group might have a power of 0.90 to detect a difference between patients receiving study drug and patients receiving placebo of 10 mg/dL or more, but only have a power of 0.70 to detect a difference of 5 mg/dL.

Placebo groups[link]

Merely giving a treatment can have nonspecific effects, and these are controlled for by the inclusion of a placebo group. Subjects in the treatment and placebo groups are assigned randomly and blinded as to which group they belong. Since researchers can behave differently to subjects given treatments or placebos, trials are also doubled-blinded so that the researchers do not know to which group a subject is assigned.

Assigning a person to a placebo group can pose an ethical problem if it violates his or her right to receive the best available treatment. The Declaration of Helsinki provides guidelines on this issue.

Phases[link]

Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases 1, 2, and 3, it will usually be approved by the national regulatory authority for use in the general population.

• Phase 1: Screening for safety
• Phase 2: Establishing the testing protocol
• Phase 3: Final testing
• Phase IV: 'Post-approval' studies

Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions:

In Phase 1 trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely.

In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies.

Length[link]

Clinical trials are only a small part of the research that goes into developing a new treatment. Potential drugs, for example, first have to be discovered, purified, characterized, and tested in labs (in cell and animal studies) before ever undergoing clinical trials. In all, about 1,000 potential drugs are tested before just one reaches the point of being tested in a clinical trial.^{[citation needed]} For example, a new cancer drug has, on average, 6 years of research behind it before it even makes it to clinical trials. But the major holdup in making new cancer drugs available is the time it takes to complete clinical trials themselves. On average, about 8 years pass from the time a cancer drug enters clinical trials until it receives approval from regulatory agencies for sale to the public. Drugs for other diseases have similar timelines.

Some reasons a clinical trial might last several years:

• For chronic conditions like cancer, it takes months, if not years, to see if a cancer treatment has an effect on a patient.
• For drugs that are not expected to have a strong effect (meaning a large number of patients must be recruited to observe any effect), recruiting enough patients to test the drug's effectiveness (i.e., getting statistical power) can take several years.
• Only certain people who have the target disease condition are eligible to take part in each clinical trial. Researchers who treat these particular patients must participate in the trial. Then they must identify the desirable patients and obtain consent from them or their families to take part in the trial.

The biggest barrier to completing studies is the shortage of people who take part. All drug and many device trials target a subset of the population, meaning not everyone can participate. Some drug trials require patients to have unusual combinations of disease characteristics. It is a challenge to find the appropriate patients and obtain their consent, especially when they may receive no direct benefit (because they are not paid, the study drug is not yet proven to work, or the patient may receive a placebo). In the case of cancer patients, fewer than 5% of adults with cancer will participate in drug trials. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), about 400 cancer medicines were being tested in clinical trials in 2005. Not all of these will prove to be useful, but those that are may be delayed in getting approved because the number of participants is so low.^[18]

For clinical trials involving a seasonal indication (such as airborne allergies, Seasonal Affective Disorder, influenza, and others), the study can only be done during a limited part of the year (such as Spring for pollen allergies), when the drug can be tested. This can be an additional complication on the length of the study, yet proper planning and the use of trial sites in the southern as well as northern hemispheres allows for year-round trials can reduce the length of the studies.^[19][20]

Clinical trials that do not involve a new drug usually have a much shorter duration. (Exceptions are epidemiological studies like the Nurses' Health Study.)

Administration[link]

Clinical trials designed by a local investigator and (in the U.S.) federally funded clinical trials are almost always administered by the researcher who designed the study and applied for the grant. Small-scale device studies may be administered by the sponsoring company. Clinical trials of new drugs are usually administered by a contract research organization (CRO) hired by the sponsoring company. The sponsor provides the drug and medical oversight. A CRO is a company that is contracted to perform all the administrative work on a clinical trial. For Phase 2, 3 and 4 the CRO recruits participating researchers, trains them, provides them with supplies, coordinates study administration and data collection, sets up meetings, monitors the sites for compliance with the clinical protocol, and ensures that the sponsor receives data from every site. Specialist site management organizations can also be hired to coordinate with the CRO to ensure rapid IRB/IEC approval and faster site initiation and patient recruitment. Phase I clinical trials of new medicines are often conducted in an specialist clinical trial clinic, with dedicated pharmacologists, where the subject can be observed by full-time staff. These clinics are often run by a CRO who specialises in these studies.

At a participating site, one or more research assistants (often nurses) do most of the work in conducting the clinical trial. The research assistant's job can include some or all of the following: providing the local Institutional Review Board (IRB) with the documentation necessary to obtain its permission to conduct the study, assisting with study start-up, identifying eligible patients, obtaining consent from them or their families, administering study treatment(s), collecting and statistically analyzing data, maintaining and updating data files during followup, and communicating with the IRB, as well as the sponsor and CRO.

Ethical conduct[link]

Clinical trials are closely supervised by appropriate regulatory authorities. All studies that involve a medical or therapeutic intervention on patients must be approved by a supervising ethics committee before permission is granted to run the trial. The local ethics committee has discretion on how it will supervise noninterventional studies (observational studies or those using already collected data). In the U.S., this body is called the Institutional Review Board (IRB). Most IRBs are located at the local investigator's hospital or institution, but some sponsors allow the use of a central (independent/for profit) IRB for investigators who work at smaller institutions.

To be ethical, researchers must obtain the full and informed consent of participating human subjects. (One of the IRB's main functions is ensuring that potential patients are adequately informed about the clinical trial.) If the patient is unable to consent for him/herself, researchers can seek consent from the patient's legally authorized representative. In California, the state has prioritized the individuals who can serve as the legally authorized representative.^[21]

In some U.S. locations, the local IRB must certify researchers and their staff before they can conduct clinical trials. They must understand the federal patient privacy (HIPAA) law and good clinical practice. International Conference of Harmonisation Guidelines for Good Clinical Practice (ICH GCP) is a set of standards used internationally for the conduct of clinical trials. The guidelines aim to ensure that the "rights, safety and well being of trial subjects are protected".

The notion of informed consent of participating human subjects exists in many countries all over the world, but its precise definition may still vary.

Informed consent is clearly a necessary condition for ethical conduct but does not ensure ethical conduct. The final objective is to serve the community of patients or future patients in a best-possible and most responsible way. However, it may be hard to turn this objective into a well-defined quantified objective function. In some cases this can be done, however, as for instance for questions of when to stop sequential treatments (see Odds algorithm), and then quantified methods may play an important role.

Additional ethical concerns are present when conducting clinical trials on children (pediatrics).

Safety[link]

Responsibility for the safety of the subjects in a clinical trial is shared between the sponsor, the local site investigators (if different from the sponsor), the various IRBs that supervise the study, and (in some cases, if the study involves a marketable drug or device) the regulatory agency for the country where the drug or device will be sold.

For safety reasons, many clinical trials of drugs are designed to exclude women of childbearing age, pregnant women, and/or women who become pregnant during the study. In some cases the male partners of these women are also excluded or required to take birth control measures.

Sponsor[link]

• Throughout the clinical trial, the sponsor is responsible for accurately informing the local site investigators of the true historical safety record of the drug, device or other medical treatments to be tested, and of any potential interactions of the study treatment(s) with already approved medical treatments. This allows the local investigators to make an informed judgment on whether to participate in the study or not.
• The sponsor is responsible for monitoring the results of the study as they come in from the various sites, as the trial proceeds. In larger clinical trials, a sponsor will use the services of a Data Monitoring Committee (DMC, known in the U.S. as a Data Safety Monitoring Board). This is an independent group of clinicians and statisticians. The DMC meets periodically to review the unblinded data that the sponsor has received so far. The DMC has the power to recommend termination of the study based on their review, for example if the study treatment is causing more deaths than the standard treatment, or seems to be causing unexpected and study-related serious adverse events.
• The sponsor is responsible for collecting adverse event reports from all site investigators in the study, and for informing all the investigators of the sponsor's judgment as to whether these adverse events were related or not related to the study treatment. This is an area where sponsors can slant their judgment to favor the study treatment.
• The sponsor and the local site investigators are jointly responsible for writing a site-specific informed consent that accurately informs the potential subjects of the true risks and potential benefits of participating in the study, while at the same time presenting the material as briefly as possible and in ordinary language. FDA regulations and ICH guidelines both require that "the information that is given to the subject or the representative shall be in language understandable to the subject or the representative." If the participant's native language is not English, the sponsor must translate the informed consent into the language of the participant.^[22]

Local site investigators[link]

• A physician's first duty is to his/her patients, and if a physician investigator believes that the study treatment may be harming subjects in the study, the investigator can stop participating at any time. On the other hand, investigators often have a financial interest in recruiting subjects, and can act unethically in order to obtain and maintain their participation.
• The local investigators are responsible for conducting the study according to the study protocol, and supervising the study staff throughout the duration of the study.
• The local investigator or his/her study staff are responsible for ensuring that potential subjects in the study understand the risks and potential benefits of participating in the study; in other words, that they (or their legally authorized representatives) give truly informed consent.
• The local investigators are responsible for reviewing all adverse event reports sent by the sponsor. (These adverse event reports contain the opinion of both the investigator at the site where the adverse event occurred, and the sponsor, regarding the relationship of the adverse event to the study treatments). The local investigators are responsible for making an independent judgment of these reports, and promptly informing the local IRB of all serious and study-treatment-related adverse events.
• When a local investigator is the sponsor, there may not be formal adverse event reports, but study staff at all locations are responsible for informing the coordinating investigator of anything unexpected.
• The local investigator is responsible for being truthful to the local IRB in all communications relating to the study.

IRBs[link]

Approval by an IRB, or ethics board, is necessary before all but the most informal medical research can begin.

• In commercial clinical trials, the study protocol is not approved by an IRB before the sponsor recruits sites to conduct the trial. However, the study protocol and procedures have been tailored to fit generic IRB submission requirements. In this case, and where there is no independent sponsor, each local site investigator submits the study protocol, the consent(s), the data collection forms, and supporting documentation to the local IRB. Universities and most hospitals have in-house IRBs. Other researchers (such as in walk-in clinics) use independent IRBs.
• The IRB scrutinizes the study for both medical safety and protection of the patients involved in the study, before it allows the researcher to begin the study. It may require changes in study procedures or in the explanations given to the patient. A required yearly "continuing review" report from the investigator updates the IRB on the progress of the study and any new safety information related to the study.

Regulatory agencies[link]

• If a clinical trial concerns a new regulated drug or medical device (or an existing drug for a new purpose), the appropriate regulatory agency for each country where the sponsor wishes to sell the drug or device is supposed to review all study data before allowing the drug/device to proceed to the next phase, or to be marketed. However, if the sponsor withholds negative data, or misrepresents data it has acquired from clinical trials, the regulatory agency may make the wrong decision.
• In the U.S., the FDA can audit the files of local site investigators after they have finished participating in a study, to see if they were correctly following study procedures. This audit may be random, or for cause (because the investigator is suspected of fraudulent data). Avoiding an audit is an incentive for investigators to follow study procedures.

Different countries have different regulatory requirements and enforcement abilities. "An estimated 40 percent of all clinical trials now take place in Asia, Eastern Europe, central and south America. "There is no compulsory registration system for clinical trials in these countries and many do not follow European directives in their operations", says Dr. Jacob Sijtsma of the Netherlands-based WEMOS, an advocacy health organisation tracking clinical trials in developing countries."^[23]

Beginning in the 1980s, harmonization of clinical trial protocols was shown as feasible across countries of the European Union. At the same time, coordination between Europe, Japan and the United States led to a joint regulatory-industry initiative on international harmonization named after 1990 as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)^[24] Currently, most clinical trial programs follow ICH guidelines, aimed at "ensuring that good quality, safe and effective medicines are developed and registered in the most efficient and cost-effective manner. These activities are pursued in the interest of the consumer and public health, to prevent unnecessary duplication of clinical trials in humans and to minimize the use of animal testing without compromising the regulatory obligations of safety and effectiveness."^[25]

Economics[link]

Sponsor[link]

The cost of a study depends on many factors, especially the number of sites that are 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 onsite 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 that patients do not feel coerced to take part in the trial by overly attractive payments)

These costs are incurred over several years.

In the U.S. there is a 50% tax credit for sponsors of certain clinical trials.^[26]

National health agencies such as the U.S. National Institutes of Health offer grants to investigators who design clinical trials that attempt to answer research questions that interest 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.^[27]

Investigators[link]

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 in between clinical trials.

Subjects[link]

In Phase 1 drug trials, participants are paid because they give up their time (sometimes away from their homes) and are exposed to unknown risks, without the expectation of any benefit. In most other trials, however, subjects are not paid, in order to ensure that 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 like travel or as compensation for their time in providing follow-up information about their health after they are discharged from medical care.

Participating in a clinical trial[link]

Phase 0 and Phase 1 drug trials seek healthy volunteers. Most other clinical trials seek patients who have a specific disease or medical condition. There is general consensus that the diversity observed in society should be reflected in clinical trials through the appropriate inclusion of ethnic minority populations.^[28]

Locating trials[link]

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 U.S. and Canada, and search for specific Parkinson's clinical trials using criteria such as location, trial type, and symptom.^[29] Other disease-specific services exist for volunteers to find trials related to their condition.^[30] 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[link]

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.^[31]

All volunteers being considered for a trial are required to undertake a medical screen. There are different requirements for different trials, but typically volunteers will have the following tests in a medical laboratory:^[32]

• 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[link]

The last decade has seen a proliferation of information technology use in the planning and conduct of clinical trials. Clinical trial management systems (CTMS) 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 (CDMS) are used in a majority of clinical trials^[33] to collect case report data from sites, manage its quality and prepare it for analysis. Interactive voice response systems (IVRS) 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 it for regulatory submission. Access to many of these applications are increasingly aggregated in web-based clinical trial portals.

Controversy[link]

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 U.S.^{[citation needed]} Researchers may be restricted from contributing to the trial design, accessing the raw data, and interpreting the results.^[34]

Seeding trials are particularly controversial.^[35]

References[link]

External links[link]

• The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
• The International Clinical Trials Registry Platform (ICTRP)
• IFPMA Clinical Trials Portal (IFPMA CTP) to Find Ongoing & Completed Trials of New Medicines
• ClinicalTrials.gov
• Clinical Trials for cancer research - National Cancer Institute

Lou Gehrig
First baseman
Born: (1903-06-19)June 19, 1903 Yorkville, New York City, New York
Died: June 2, 1941(1941-06-02) (aged 37) Riverdale, New York City, New York
Batted: Left	Threw: Left
MLB debut
June 15, 1923 for the New York Yankees
Last MLB appearance
April 30, 1939 for the New York Yankees
Career statistics
Batting average	.340
Home runs	493
Hits	2,721
Runs batted in	1,995
Teams
New York Yankees (1923–1939)
Career highlights and awards
7× All-Star (1933, 1934, 1935, 1936, 1937, 1938, 1939) 6× World Series champion (1927, 1928, 1932, 1936, 1937, 1938) 2× AL MVP (1927, 1936) Hit four home runs in one game on June 3, 1932 New York Yankees team captain (1935–1939) New York Yankees #4 retired Major League Baseball All-Century Team Major League Baseball All-Time Team Other accomplishments
Member of the National
Baseball Hall of Fame
Induction	1939
Vote	Special Election (results unknown)

Henry Louis "Lou" or "Buster"^[1] Gehrig (June 19, 1903 – June 2, 1941) was an American baseball first baseman who played 17 seasons in Major League Baseball (MLB) for the New York Yankees (1923–1939). Gehrig set several major league records,^[2] including most career grand slams (23)^[3] and most consecutive games played (2,130). Gehrig is chiefly remembered for his prowess as a hitter and his durability, a trait which earned him his nickname "The Iron Horse", as well as the pathos of his farewell from baseball at age 36, when he was stricken with amyotrophic lateral sclerosis (ALS). Gehrig was elected to the Baseball Hall of Fame in 1939. In 1969 he was voted the greatest first baseman of all time by the Baseball Writers' Association,^[4] and was the leading vote-getter on the Major League Baseball All-Century Team, chosen by fans in 1999.^[5]

A native of New York City, he played for the Yankees until his career was cut short by ALS, a disorder now commonly known in the United States and Canada as Lou Gehrig's disease.^[6] Over a 15-season span from 1925 through 1939, he played in 2,130 consecutive games. This streak ended only when Gehrig became disabled by the fatal neuromuscular disease that claimed his life two years later. His streak, long considered one of baseball's few unbreakable records,^[7] stood for 56 years, until finally broken by Cal Ripken, Jr., of the Baltimore Orioles on September 6, 1995.

Gehrig accumulated 1,995 runs batted in (RBIs) in 17 seasons, with a career batting average of .340, on-base percentage of .447, and slugging percentage of .632. Three of the top six RBI seasons in baseball history belong to Gehrig. He was selected to each of the first seven All-Star games (though he did not play in the 1939 game, as he retired one week before it was held),^[8] and he won the American League's (AL) Most Valuable Player (MVP) Award in 1927 and 1936. He was also a Triple Crown winner in 1934, leading the AL in batting average, home runs, and RBIs.^[9]

Early life[link]

Gehrig was born in the East Harlem section of Manhattan at 1994 Second Avenue,^[10] weighing almost 14 pounds (6.4 kg) at birth, the second child out of four to German immigrants.^[11] His father Heinrich was a sheet metal worker by trade, but frequently unemployed due to alcoholism, and his mother Christina was a maid, the main breadwinner and disciplinarian in the family.^[12] His two sisters died from whooping cough and measles at an early age; another son also died in infancy.^[13] Young Gehrig helped his mother with her work, doing tasks such as folding laundry and picking up supplies from the local stores.^[14] In 1910, Gehrig lived with his parents at 2266 Amsterdam Avenue in Manhattan.^[15] In 1920 the family resided at 2079 8th Avenue in Manhattan.^[16]

Gehrig on the Columbia University baseball team

Gehrig first garnered national attention for his baseball ability while playing in a game at Cubs Park (now Wrigley Field) on June 26, 1920. Gehrig's New York School of Commerce team was playing a team from Chicago's Lane Tech High School, in front of a crowd of more than 10,000 spectators.^[17] With his team winning 8–6 in the top of the ninth inning, Gehrig hit a grand slam completely out of the major league park, an unheard-of feat for a 17-year old.^[17][18]

Lou Gehrig attended PS 132 in the Washington Heights section of Manhattan, then to Commerce High School, graduating in 1921.^[19][20] Gehrig then studied at Columbia University for two years, although he did not graduate.^[21] While attending Columbia, he was a member of Phi Delta Theta fraternity.^[22] Initially, Gehrig could not play intercollegiate baseball for the Columbia Lions because he had played baseball for the minor-league Hartford Senators of the Eastern League in the summer before his freshman year.^[22] At the time, he was unaware that doing so jeopardized his eligibility to play any collegiate sport. However, Gehrig was ruled eligible to play on the Lions' football team and was a standout fullback. Later, he gained baseball eligibility and played on the Lions team.

On April 18, 1923, the same day that Yankee Stadium opened for the first time and Babe Ruth inaugurated the new stadium with a home run, Columbia pitcher Gehrig struck out seventeen Williams College batters to set a team record; however, Columbia lost the game. Only a handful of collegians were at South Field that day, but more significant was the presence of Yankee scout Paul Krichell, who had been trailing Gehrig for some time. It was not Gehrig’s pitching that particularly impressed him; rather, it was Gehrig’s powerful left-handed hitting. During the time Krichell had been observing the young Columbia ballplayer, Gehrig had hit some of the longest home runs ever seen on various Eastern campuses, including a 450-foot (137 m) home run on April 28 at Columbia's South Field which landed at 116th Street and Broadway.^[23] Within two months, Gehrig had signed a Yankee contract.^[22] Gehrig returned to minor-league Hartford to play parts of two seasons, 1923 and 1924, batting .344 and crushing 61 home runs in 193 games. (It was the only time Lou ever played any level of ball—sandlot, high school, collegiate or pro—for a non-New York City-based team.)

Major League career[link]

Gehrig joined the New York Yankees midway through the 1923 season and made his debut on June 15, 1923, as a pinch hitter. In his first two seasons, he saw limited playing time, mostly as a pinch hitter — he played in only 23 games and was not on the Yankees' 1923 World Series roster. In 1925, he batted .295, with 20 home runs and 68 runs batted in (RBIs).^[24]

Babe Ruth and Lou Gehrig in exhibition game at West Point, New York (May 6, 1927)

The 23-year-old Yankee first baseman's breakout season came in 1926, when he batted .313 with 47 doubles, an American League-leading 20 triples, 16 home runs, and 112 RBIs.^[24] In the 1926 World Series against the St. Louis Cardinals, Gehrig hit .348 with two doubles and 4 RBIs. The Cardinals won a seven-game series four games to three.^[25]

In 1927, Gehrig put up one of the greatest seasons by any batter in history, hitting .373, with 218 hits: 52 doubles, 18 triples, 47 home runs, a then-record 175 runs batted in (surpassing teammate Babe Ruth's 171 six years earlier), and a .765 slugging percentage.^[24] His 117 extra-base hits that season are second all-time to Babe Ruth’s 119 extra-base hits in 1921^[24] and his 447 total bases are third all-time, after Babe Ruth's 457 total bases in 1921 and Rogers Hornsby's 450 in 1922.^[24] Gehrig's production helped the 1927 Yankees to a 110–44 record, the AL pennant, and a four-game sweep of the Pittsburgh Pirates in the 1927 World Series. Although the AL recognized his season by naming him league MVP, it was overshadowed by Babe Ruth’s 60 home run season and the overall dominance of the 1927 Yankees, a team often cited as having the greatest lineup of all time — the famed Murderers' Row.^[26]

Despite playing in the shadow of the larger-than-life Ruth for two-thirds of his career, Gehrig was one of the highest run producers in baseball history: he had 509 RBIs during a three-season stretch (1930–32). Only two other players, Jimmie Foxx with 507 and Hank Greenberg with 503, have surpassed 500 RBIs in any three seasons; their totals were non-consecutive. (Babe Ruth had 498.)^[27] Playing 14 complete seasons, Gehrig had 13 consecutive seasons with 100 or more RBIs (a major league record shared with Foxx until eclipsed in 2010 by Alex Rodriguez). Gehrig had six seasons where he batted .350 or better (with a high of .379 in 1930), plus a seventh season at .349. He had seven seasons with 150 or more RBIs, 11 seasons with over 100 walks, eight seasons with 200 or more hits, and five seasons with more than 40 home runs.^[28] Gehrig led the American League in runs scored four times, home runs three times, and RBIs five times. His 184 RBIs in 1931 remain the American League record as of 2010 and rank second all-time to Hack Wilson's 191 RBIs in 1930. On the single-season RBI list, Gehrig ranks second, fifth (175), and sixth (174), with four additional seasons over 150 RBI. He also holds the baseball record for most seasons with 400 total bases or more, accomplishing this feat five times in his career.^[28] He batted fourth in the lineup to Ruth's third in the order, making it impractical to give up an intentional walk to Ruth.

During the 10 seasons (1925–1934) in which Gehrig and Ruth were both Yankees and played a majority of the games, Gehrig had more home runs than Ruth only once, in 1934, when he hit 49 compared to Ruth’s 22 (Ruth played 125 games that year). They tied at 46 in 1931. Ruth had 424 home runs compared to Gehrig’s 347. However, Gehrig outpaced Ruth in RBI, 1,436 to 1,316. Gehrig had a .343 batting average, compared to .338 for Ruth.^[29]

Gehrig 1933 Goudey baseball card.

In 1932, Gehrig became the first player of the 20th century to hit four home runs in a game, accomplishing the feat on June 3 against the Philadelphia Athletics.^[30] He narrowly missed getting a fifth home run in the game when Athletics center fielder Al Simmons made a leaping catch of another fly ball at the center field fence. After the game, manager Joe McCarthy told him, "Well, Lou, nobody can take today away from you." On the same day, however, John McGraw announced his retirement after thirty years of managing the New York Giants. McGraw, not Gehrig, got the main headlines in the sports sections the next day.^[31] The following year, in September 1933, Gehrig married Eleanor Twitchell, the daughter of Chicago Parks Commissioner Frank Twitchell.^[24]

In a 1936 World Series cover story about Lou Gehrig and Carl Hubbell, Time proclaimed Gehrig "the game's No. 1 batsman", who "takes boyish pride in banging a baseball as far, and running around the bases as quickly, as possible".^[32]

2,130 consecutive games[link]

Seven of the American League's 1937 All-Star players, from left to right Lou Gehrig, Joe Cronin, Bill Dickey, Joe DiMaggio, Charlie Gehringer, Jimmie Foxx and Hank Greenberg. All seven would eventually be elected to the Hall of Fame.

On June 1, 1925, Gehrig entered the game as a pinch hitter, substituting for shortstop Paul "Pee Wee" Wanninger. The next day, June 2, Yankee manager Miller Huggins started Gehrig in place of regular first baseman Wally Pipp. Pipp was in a slump, as were the Yankees as a team, so Huggins made several lineup changes to boost their performance. Fourteen years later, Gehrig had played 2,130 consecutive games. In a few instances, Gehrig managed to keep the streak intact through pinch hitting appearances and fortuitous timing; in others, the streak continued despite injuries. For example:

• On April 23, 1933, a pitch by Washington Senators pitcher Earl Whitehill struck Gehrig in the head. Although almost knocked unconscious, Gehrig remained in the game.
• On June 14, 1933, Gehrig was ejected from a game, along with manager Joe McCarthy, but he had already been at bat and received credit for playing the game.
• On July 13, 1934, Gehrig suffered a "lumbago attack" and had to be assisted off the field. In the next day's away game, he was listed in the lineup as "shortstop", batting lead-off. In his first and only plate appearance, he singled and was promptly replaced by a pinch runner to rest his throbbing back, never taking the field. A&E's Biography speculated that this illness, which he also described as "a cold in his back", might have been the first symptom of his debilitating disease.^[33]

In addition, X-rays taken late in his life disclosed that Gehrig had sustained several fractures during his playing career, although he remained in the lineup despite those previously undisclosed injuries.^[34] On the other hand, the streak was helped when Yankees general manager Ed Barrow postponed a game as a rainout on a day when Gehrig was sick with the flu—even though it was not raining.^[35]

Gehrig's record of 2,130 consecutive games played stood until September 6, 1995, when Baltimore Orioles shortstop Cal Ripken, Jr. broke it.^[36]

Illness[link]

Although his performance in the second half of the 1938 season was slightly better than in the first half, Gehrig reported physical changes at the midway point. At the end of that season, he said, "I tired mid-season. I don't know why, but I just couldn't get going again." Although his final 1938 statistics were above average (.295 batting average, 114 RBI, 170 hits, .523 slugging percentage, 689 plate appearances with only 75 strikeouts, and 29 home runs), they were significantly down from his 1937 season, in which he batted .351 and slugged .643. In the 1938 World Series, he had four hits in 14 at-bats, all singles.^[37]

When the Yankees began their 1939 spring training in St. Petersburg, Florida, it was clear that Gehrig no longer possessed his once-formidable power. Even Gehrig's base running was affected, and at one point he collapsed at Al Lang Field, then the Yankees' spring training park.^[38] By the end of spring training, Gehrig had not hit a home run.^[39] Throughout his career, Gehrig was considered an excellent baserunner, but as the 1939 season got under way, his coordination and speed had deteriorated significantly.^[40]

By the end of April, his statistics were the worst of his career, with one RBI and a .143 batting average. Fans and the press openly speculated on Gehrig's abrupt decline. James Kahn, a reporter who wrote often about Gehrig, said in one article:

I think there is something wrong with him. Physically wrong, I mean. I don't know what it is, but I am satisfied that it goes far beyond his ball-playing. I have seen ballplayers 'go' overnight, as Gehrig seems to have done. But they were simply washed up as ballplayers. It's something deeper than that in this case, though. I have watched him very closely and this is what I have seen: I have seen him time a ball perfectly, swing on it as hard as he can, meet it squarely — and drive a soft, looping fly over the infield. In other words, for some reason that I do not know, his old power isn't there... He is meeting the ball, time after time, and it isn't going anywhere.^[41]

He was indeed meeting the ball, with only one strikeout in 28 at-bats; however, Joe McCarthy found himself resisting pressure from Yankee management to switch Gehrig to a part-time role. Things came to a head when Gehrig had to struggle to make a routine put-out at first base. The pitcher, Johnny Murphy, had to wait for Gehrig to drag himself over to the bag so he could field the throw. Murphy said, "Nice play, Lou."^[41]

On April 30, Gehrig went hitless against the Washington Senators. Gehrig had just played his 2,130th consecutive major league game.^[29]

On May 2, the next game after a day off, Gehrig approached McCarthy before the game in Detroit against the Tigers and said, "I'm benching myself, Joe," telling the Yankees' skipper that he was doing so "for the good of the team."^[42] McCarthy acquiesced, putting Ellsworth "Babe" Dahlgren in at first base, and also said that whenever Gehrig wanted to play again, the position was his. Gehrig himself took the lineup card out to the shocked umpires before the game, ending the fourteen-year streak. Before the game began, the Briggs Stadium announcer told the fans, "Ladies and gentlemen, this is the first time Lou Gehrig's name will not appear on the Yankee lineup in 2,130 consecutive games." The Detroit Tigers' fans gave Gehrig a standing ovation while he sat on the bench with tears in his eyes.^[37] A wire service photograph of Gehrig reclining against the dugout steps with a stoic expression appeared the next day in the nation's newspapers. Other than his retirement ceremony, it is one of the most-reproduced and best-remembered visual images of Gehrig.

Gehrig stayed with the Yankees as team captain for the rest of the season, but never played in a major league game again.^[37]

Diagnosis[link]

As Lou Gehrig's debilitation became steadily worse (he stumbled over curbs, mishandled fielding plays, and fell while running the bases), his wife, Eleanor, called the famed Mayo Clinic in Rochester, Minnesota. Her call was transferred to Charles William Mayo, who had been following Gehrig's career and his mysterious loss of strength. Mayo told Eleanor to bring Gehrig as soon as possible.^[37]

Eleanor and Gehrig flew to Rochester from Chicago, where the Yankees were playing at the time, arriving at the Mayo Clinic on June 13, 1939. After six days of extensive testing at Mayo Clinic, the diagnosis of amyotrophic lateral sclerosis (ALS) was confirmed on June 19, Gehrig's 36th birthday.^[11] The prognosis was grim: rapidly increasing paralysis, difficulty in swallowing and speaking, and a life expectancy of less than three years, although there would be no impairment of mental functions. Eleanor Gehrig was told that the cause of ALS was unknown but it was painless, non-contagious and cruel — the motor function of the central nervous system is destroyed but the mind remains fully aware to the end.^[43][44]

At Eleanor's request, the Mayo doctors intentionally withheld his grim prognosis from Gehrig. He often wrote letters to Eleanor, and in one such note written shortly afterwards, said (in part):

The bad news is lateral sclerosis, in our language chronic infantile paralysis. There isn't any cure... there are very few of these cases. It is probably caused by some germ...Never heard of transmitting it to mates... There is a 50–50 chance of keeping me as I am. I may need a cane in 10 or 15 years. Playing is out of the question...^[45]

Following Gehrig's visit to the Mayo Clinic, he briefly rejoined the Yankees in Washington, D.C. As his train pulled into Union Station, he was greeted by a group of Boy Scouts, happily waving and wishing him luck. Gehrig waved back, but he leaned forward to his companion, a reporter, and said, "They're wishing me luck — and I'm dying."^[11]

"The Luckiest Man on the Face of the Earth"[link]

Lou Gehrig's number 4 was retired by the New York Yankees in 1940.

On June 21, the New York Yankees announced Gehrig's retirement and proclaimed July 4, 1939, "Lou Gehrig Appreciation Day" at Yankee Stadium. Between games of the Independence Day doubleheader against the Washington Senators, the poignant ceremonies were held on the diamond. In its coverage the following day, The New York Times said it was "perhaps as colorful and dramatic a pageant as ever was enacted on a baseball field [as] 61,808 fans thundered a hail and farewell."^[46] Dignitaries extolled the dying slugger and the members of the 1927 Yankees World Championship team, known as "Murderer's Row", attended the ceremonies. New York Mayor Fiorello La Guardia called Gehrig "the greatest prototype of good sportsmanship and citizenship" and Postmaster General James Farley concluded his speech by predicting, "For generations to come, boys who play baseball will point with pride to your record."^[46]

Yankees Manager Joe McCarthy, struggling to control his emotions, then spoke of Lou Gehrig, with whom there was a close, almost father and son-like bond. After describing Gehrig as "the finest example of a ballplayer, sportsman, and citizen that baseball has ever known", McCarthy could stand it no longer. Turning tearfully to Gehrig, the manager said, "Lou, what else can I say except that it was a sad day in the life of everybody who knew you when you came into my hotel room that day in Detroit and told me you were quitting as a ballplayer because you felt yourself a hindrance to the team. My God, man, you were never that."^[47]

The Yankees retired Gehrig's uniform number "4", making him the first player in Major League Baseball history to be accorded that honor.^[48] Gehrig was given many gifts, commemorative plaques, and trophies. Some came from VIPs; others came from the stadium's groundskeepers and janitorial staff. Footage of the ceremonies shows Gehrig being handed various gifts, and immediately setting them down on the ground, because he no longer had the arm strength to hold them.^[11] The Yankees gave him a silver trophy with their signatures engraved on it. Inscribed on the front was a special poem written by The New York Times writer John Kieran.^[49] The trophy cost only about $5, but it became one of Gehrig's most prized possessions.^[50] It is currently on display at the National Baseball Hall of Fame and Museum.

After the presentations and remarks by Babe Ruth, Gehrig addressed the crowd:

The crowd stood and applauded for almost two minutes. Gehrig was visibly shaken as he stepped away from the microphone, and wiped the tears away from his face with his handkerchief.^[50] Babe Ruth came over and hugged him as a band played "I Love You Truly" and the crowd chanted "We love you, Lou." The New York Times account the following day called it "one of the most touching scenes ever witnessed on a ball field", that made even hard-boiled reporters "swallow hard."^[46]

In December 1939, Lou Gehrig was elected to the National Baseball Hall of Fame and Museum in a special election by the Baseball Writers Association.^[52] At age 36, he was the second youngest player to be so honored (behind Sandy Koufax).^[53]

Final years[link]

"Don't think I am depressed or pessimistic about my condition at present," Lou Gehrig wrote following his retirement from baseball. Struggling against his ever-worsening physical condition, he added, "I intend to hold on as long as possible and then if the inevitable comes, I will accept it philosophically and hope for the best. That's all we can do."^[11]

Lou Gehrig Way in New Rochelle, NY

In October 1939, he accepted Mayor LaGuardia's appointment to a ten-year term as a New York City Parole Commissioner and was sworn into office on January 2, 1940.^[52] The Parole Commission commended the ex-ballplayer for his "firm belief in parole, properly administered", stating that Gehrig "indicated he accepted the parole post because it represented an opportunity for public service. He had rejected other job offers – including lucrative speaking and guest appearance opportunities – worth far more financially than the $5,700 a year commissionership." Gehrig visited New York City's correctional facilities, but insisted that the visits not be covered by news media.^[54] Gehrig, as always, quietly and efficiently performed his duties. He was often helped by his wife Eleanor, who would guide his hand when he had to sign official documents. About a month before his death, when Gehrig reached the point where his deteriorating physical condition made it impossible for him to continue in the job, he quietly resigned.^[55]

On June 2, 1941, at 10:10 p.m., sixteen years to the day after he replaced Wally Pipp at first base and two years after his retirement from baseball, Lou Gehrig died at his home in the Riverdale section of the Bronx, New York.^[56][57]

Upon hearing the news, Babe Ruth and his wife Claire went to the Gehrig house to console Eleanor. Mayor LaGuardia ordered flags in New York to be flown at half-staff, and Major League ballparks around the nation did likewise.^[58]

Following the funeral at Christ Episcopal Church of Riverdale, Gehrig's remains were cremated and interred on June 4 at Kensico Cemetery in Valhalla, New York. Lou Gehrig and Ed Barrow are both interred in the same section of Kensico Cemetery, which is next door to Gate of Heaven Cemetery, where the graves of Babe Ruth and Billy Martin are located.^[59]

Lou Gehrig's headstone in Kensico Cemetery (the year of his birth was inscribed erroneously as 1905)

The Gehrigs had no children. Eleanor, who never remarried, dedicated the remainder of her life to supporting ALS research. She died on March 6, 1984, on her 80th birthday.^[18]

The Yankees dedicated a monument to Gehrig in center field at Yankee Stadium on July 6, 1941, the shrine lauding him as, "A man, a gentleman and a great ballplayer whose amazing record of 2,130 consecutive games should stand for all time." Gehrig's monument joined the one placed there in 1932 to Miller Huggins, which would eventually be followed by Babe Ruth's in 1949.^[29]

Gehrig's birthplace in Manhattan, at 1994 Second Avenue (near E. 103rd Street), is memorialized with a plaque marking the site, as is another early residence on E. 94th Street (near Second Avenue). (As of 26/12/2011, the first mentioned plaque is not present due to ongoing construction. The second mentioned plaque is present, but ascribes to his birthplace, not early residence.) The Gehrigs' white house at 5204 Delafield Avenue in the Riverdale section of the Bronx, where Lou Gehrig died, still stands today on the east side of the Henry Hudson Parkway and is likewise marked by a plaque.^[24]

Records, awards, and accomplishments[link]

Sixty years after his farewell to baseball, Gehrig received the most votes of any baseball player on the Major League Baseball All-Century Team, chosen by fan balloting in 1999.^[5]

Records[link]

Gehrig sliding into home plate in 1925.

Awards and honors[link]

Other accomplishments[link]

Film and other media[link]

Gehrig in "Rawhide"

Lou Gehrig starred in the 1938 20th Century Fox movie Rawhide playing himself in his only feature film appearance.^[64] In 2006, researchers presented a paper to the American Academy of Neurology, reporting on an analysis of Rawhide and photographs of Lou Gehrig from the 1937–1939 period, to ascertain when Gehrig began to show visible symptoms of amyotrophic lateral sclerosis. They concluded that while atrophy of hand muscles could be detected in 1939 photographs of Gehrig, no such abnormality was visible at the time Rawhide was made in January 1938. "Examination of Rawhide showed that Gehrig functioned normally in January 1938", the report concluded.^[65]

In 1942, the life of Lou Gehrig was portrayed in the movie The Pride of the Yankees, starring Gary Cooper as Gehrig and Teresa Wright as his wife Eleanor. It received 11 Academy Award nominations and won in one category, Film Editing. Real-life Yankees Babe Ruth, Bob Meusel, Mark Koenig and Bill Dickey (then still an active player) played themselves, as did sportscaster Bill Stern.

Later, in 1978, a TV movie, A Love Affair: The Eleanor and Lou Gehrig Story was released, starring Blythe Danner and Edward Herrmann as Eleanor and Lou Gehrig. It was based on the 1976 autobiography My Luke and I, written by Eleanor Gehrig and Joseph Durso.

In an episode of the PBS series Jean Shepherd's America, the Chicago-born Shepherd told of how he and his father (Jean Shepherd, Sr.) would watch Chicago White Sox games from the right field upper deck at Comiskey Park in the 1930s. On one occasion, the Sox were playing the Yankees, and Shepherd Sr. had been taunting Gehrig, yelling at him all day. In the top of the ninth, with Sox icon Ted Lyons holding a slim lead, Gehrig came up with a man on base, and the senior Shepherd yelled in a voice that echoed around the ballpark, "Hit one up here, ya bum! I dare ya!" Gehrig did exactly that, hitting a screaming liner, practically into the heckler's lap, for the eventual game-winning home run. Shepherd's father was booed mercilessly, and he never again took junior Jean to a game. He apparently told this story originally when Gehrig's widow was in the audience at a speaking engagement.^[66]

See also[link]

	Biography portal
	Baseball portal
	New York City portal

References[link]

External links[link]

Wikimedia Commons has media related to: Lou Gehrig

Wikiquote has a collection of quotations related to: Lou Gehrig

• YouTube Video of Lou Gehrig - Superman
• Lou Gehrig at the Baseball Hall of Fame
• Career statistics and player information from Baseball-Reference, or Fangraphs, or The Baseball Cube, or Baseball-Reference (Minors)
• Video, Audio and Text of Lou Gehrig's Farewell to Baseball Address
• Official Website
• Gehrig's shining legacy of courage, Major League Baseball tribute by Mark Newman on Gehrig's 100th birthday.
• Lou Gehrig Memorial at Find a Grave