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India as a site for conducting clinical trials
Related to country: India
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INTRODUCTION
Clinical research is an indispensable part of the drug discovery process to ensure the safety and efficacy of any new drug. In today’s global scientific era, clinical trials are the mainstay for bringing newer and better drugs to market.

What is a clinical trial?
Clinical trials are experiments to determine the value of treatments. There are two key components to the experimental approach. First, results rather than plausible reasoning are required to support conclusions. Second, experiments should be prospectively planned and conducted under controlled conditions in order to provide definitive answers to well defined questions.

Development of new drug involves two phases, namely drug discovery and drug development. The stage of drug discovery involves the identification of the target, drug designing and synthesis followed by its preliminary invitro screening.

The next step is preclinical evaluation, which involves rigorous testing of efficacy and safety of the new molecule by various in vivo assays using animals. The necessary data for evaluation in humans is generated here and the test drug is now ready for its last and most crucial stage of evaluation i.e., clinical evaluation.
The clinicians in coordination with the pharmacists evaluates the efficacy and the safety of the sample over four stages starting from healthy volunteers and moving onto small group of patients and then larger number of patients and special groups. Phase - I or clinical pharmacology forms the basis for clinical trial for any new drug and provides the link between pre clinical and clinical research (Kuhlmann, 1997). Finally, the application for regulatory review and approval may be applied and the approval sought.








Defination:
According to ICH-GCP
Clinical trial/study:
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial and clinical study are synonymous.

According to Indian-GCP
Clinical trial: A systematic study of pharmaceutical products on human subjects – (whether patients or non-patient volunteers) – in order to discover or verify the clinical, pharmacological (including / pharmacokinetics), and adverse effects, with the object of determining their safety and efficacy.

Scope of Clinical Research
Every new drug evidence from clinical research to support its launch. Thus, whether it is a new chemical entity or an existing drug that is being marketed for new indication, clinical studies have to be conducted. Similarly, launch of new formulations, drug delivery systems or even new fixed dose combination, requires clinical data before it can be marketed. Hence it is obvious that the area of clinical research holds immense scope and promise for without the supporting data, drug launch is not feasible. The conduct of clinical research is based on the GCP and ICH guidelines.

HISTORY OF CLINICAL TRIAL:
Sure, science involves trial and error. Scientists refine theories each day. But as they do, they help us grasp more clearly the wonders of the world and the universe.
Tony Snow




The history of Drug discovery is often fascinating. Many of the drugs that are used today have been discovered by chance or often by mere serendipity. India’s history of drug discovery and proficiency in Medical Research can be traced back to two ancient scripts, Charaka Samhita (a textbook of medicine) and Sushruta Samhita (a textbook of surgery), compiled as early as 200 B. C. and 200 A. D. respectively.

Clinical Trials Timeline (605 BC – 2000AD)
Clinical trial progress is depending on the progress of Science and Technology and Pharmacokinetics have all contributed to refining and redefining the whole process. The International Conference on Harmonization (ICH) meets from time to time to form and revise guidelines as per Good Clinical Practice.
A current 21st century drug discovery method has used some advanced technology. The biological revolution has given rise to many new and promising disciplines such as Nanotechnology, Pharmacometabonomic, Genomics, Proteomics, Metabolomines and Bioinformatics. Randomized controlled trial and Multicentric trial study is new design of clinical trial.
India Background:
Until recently, there were few clinical trials conducted in India by western pharmaceutical and biotech companies, primarily because of regulatory hurdles. In January 2005, recognizing the significant advantages that India offers to multinational companies and the potential and benefits of conducting clinical trials in India, the government of India upgraded schedule Y of the Drugs and Cosmetics Act of India, the equivalent of the sections of the code of Federal regulations applicable to the FDA, to harmonize it with U.S. and International Conference on Harmonization (ICH) standards. These changes removed a number of regulatory barriers to perform clinical trials in India. The changes formalized the definition and conduct of clinical trials; specified the responsibilities of the sponsor, the investigators and the Ethics Committees; developed guidelines and procedures for importing drugs for



Clinical trials; instituted required compliance with GCP; specified the requirements for informed consent; and defined the structure, content and formats of clinical study reports. In addition, the Indian Government provided increased protection for intellectual property (IP).

Indian Guideline for Clinical Trial:
After the achievement of Independence in 1947 from the British Empire, it has developed a drug regulation system that refused to allow clinical testing for therapies of foreign origin. After Independence Indian government was adopting and revised Drug and Cosmetic Act 1948. Indian regulatory systems have gradually opened up the country to foreign drug development, with the first Good Clinical Practices (GCP) trial being initiated in 1995. This guideline is called as Indian-GCP. The clinical trials legislative requirements are guided by specifications of schedule Y of Drugs and Cosmetics Act in India. Recently the Ministry of Health, along with DCGI and ICMR has come out with draft guidelines for research in human subjects. These are essentially based on Declaration of Helsinki, WHO guidelines and ICH requirements for GCP.
All clinical trials are conducted in India according to Indian-GCP and Schedule Y. Indian Clinical Research focus is shifting from cost advantages to quality and rapid response.

India Projections:
The cost per patient for trials in India is approximately 40 to 60% of the cost in western nations. More importantly, patient recruitment can be greatly accelerated, and this provides a major advantage in terms of shortening the time to market for a new drug. Based on these advantages, the number of clinical trials in India is expected to grow exponentially over the next five to ten years. It has been estimated that in 2005 only 1% of global clinical trials were conducted in India, this percentage is projected to grow to 15% of global trials by 2011. The charts below illustrate the effects of such rapid growth, projecting that by the year 2011 over 300,000 patients will be enrolled in clinical trials in India. Mckinsey projects that within five years 1,500 to 2,000 GCP studies will be conducted in India per


Year, requiring 10,000 to 15,000 GCP- trained investigators, and supported by 50,000 clinical research professionals.













Various Types of Clinical Trials being conducted in India:
Trials are on for drug which is indicated for reduction of mortality in adult patients and can be used for sepsis. Clinical Trials have already been held on more than 600 patients for human insulin and insulin. Clinical Trials are being conducted on oncology and developing a new molecule for lung cancer.

Clinical trials are on 300 patients on a new malaria 'cocktail' drug that combines chloroquine (to which Indian malarial strains have developed resistance) and azithromycin, an antibiotic. Clinical Trials are also being conducted for drugs to treat osteoporosis, breast cancer and schizophrenia.

Global trials are on in India for treatment of a particular variant of lung cancer. One of the reasons for considering India is that it has a vast patient population infected by this type of lung cancer, which is primarily triggered by use of tobacco products. India is also being considered a prospective site for future clinical trials involving new drugs and therapies for treatment of different variants of blood cancer and colorectal diseases.

The trials in India are mostly in different areas like oncology, endocrinology, traumatology, sports medicine, pulmonary diseases, pediatric diseases, and infectious diseases.

The largest Clinical Trial outside US for a drug delivery device has been conducted in India.













Status of clinical trial in India:

The Indian pharmaceutical industry is one of the fastest growing sectors of the Indian economy and has made rapid strides over the years. From being an import dependent industry in the 1950’s, the industry has achieved self-sufficiency and gained global recognition as a producer of low cost high quality bulk drugs and formulations. Having proved its mettle in the international market, India is now on the helm of taking up the challenge of proving its efficiency as the capital for global clinical trails. A number of factors favour the recognition of India as a hub for clinical research, due to which the multinational companies have identified it as their ideal destination, but In 1988, the government made it mandatory for all new drug introductions as a regulatory requirement for getting NCE’s approved. Schedule Y stipulated that the fist applicant for any new drug should generate data in local clinical trials conducted in approximately 100 patients at 4 to 5 centers. This schedule also indicates that permission for such clinical trials would be given for one phase behind the development status in the rest of the world. However, for a second and subsequent applicant for the same compound, no clinical trial would be required, since they could show bio-equivalence to the first product approved and introduces their brand of the generic in the market. Due to this lack of protection, innovator companies have been losing money by virtue of not being able to introduce their new and cutting edge research in the Indian market due to the presence of generic brands of innovator compounds.
Moreover, it also discouraged the pharmaceutical companies from carrying out global clinical studies by their local subsidiaries in India and preferred to wait for their innovator brands to be approved in source countries and then carry out limited bridging studies for local approvals. Consequently, there has been a gap between their introductions in India with the rest of the markets worldwide.








Table 1: Transition in regulatory authority capabilities in India

Before 2005 After 2005
Process patent law Product patent for drugs, food and agro chemicals
Phase II and III trials were only permitted after those phases were completed elsewhere (Phase lag)








Schedule Y amended for multi-centric concurrent clinical trials as per GCP upgraded schedule M.
Clinical trial registry - India (CTRI), funded jointly by DST, WHO and ICMR initiated.
GLP monitoring authority setup for pre-clinical (toxicological) studies.
New Drugs, imports, clinical trials, drug standards approved by central government enforcement by states.
CDSCO-WHO National pharmacovigilance program launched.



























Product patent regime:
The draft National Pharmaceuticals Policy 2006 is committed to making Indian laws and policies relating to IPR, including data protection, fully complaint with TRIPS provisions. India has signed the Trade Related Intellectual Property Rights (TRIPS) agreement as a part of the WTO regulations, which will guarantee Intellectual Property Rights and patent protection to companies holding the patent from 2005. In the present Intellectual Property Right (IPR) regime, it has become extremely important for conducting timely clinical research. Increasingly, permission for phase-I trials is being granted after thorough appraisal of the protocols, products and claims. Favorably, the government has also relaxed the duties that are levied on clinical trials samples. These steps indicate the commitment of the government in strengthening India’s position and propelling it as world leader in clinical research.


Bioethics:
While conducting the clinical trials, the CRO’s need to bear the following principle’s in mind-essentiality, voluntariness, informed consent, non-exploitation, privacy, risk minimization, professional competence, accountability, maximization of public interest and totality of responsibility and compliance (ICMR,2000). The proposed clinical trial has to be reviewed and approved by Institutional Ethics Committee (IEC), or Institutional Review Board (IRB). Following ethical approval, the proposal has to be submitted for approval to Drugs Controller General of India (DCGI), as is necessary under the schedule Y of Drugs and Cosmetics Act, 1940.
In January 2005, India adopted a new rule that will allow pharmaceutical companies to begin phase II and III trials concurrently with trials of the same phase conducted abroad, there by reducing clinical development time. Under the old rule, phase II and III trials were only permitted after those phases were completed elsewhere. The rules were intended to create a “phase lag” between India and the rest of the world to prevent foreign pharmaceutical companies from using Indians to test their unproven therapies. With the latest amendment (20th January 2005) to the schedule Y of Drugs and Cosmetic Act


1945, the reporting of adverse events from clinical trials has become clearer and unambiguous. There is of course a quantum leap between the old and the new version and the serious intentions of the DCGI regarding stricter compliance are clearly palpable.


ICH-GCP compliance:
Good clinical practices (GCP) is an ethical and scientific quality standard for designing, conducting and recording trials that involve the participation of human subjects. Compliance with this standard provides assurance to public that the rights, safety and well being of trial subjects are protected. High level of International Conference on Harmonization (ICH) of technical requirements for registration of pharmaceuticals for human use, Good Clinical Practice (GCP) and US Food and Drug Administration (FDA) standards compliance-since 2001, the DCGI has implemented conformity to ICH GCP/Good Laboratory Practice (GLP) guidelines. Generally, most competent authorities (CA s), including the FDA, will find the standards of Indian clinical trials acceptable.

Clinical trial registry:
Two independent incidents underscored the need to have a serious re-look at the way clinical trials are conducted and reported. An early stage trial of TGN1412, a monoclonal antibody to treat leukemia, went seriously wrong in Britain with a dozen patients hospitalized due to multiple organ failure necessitating hospitalization. Coming as it did close on the heels of the intense controversy that Merck with held critical data from trials of vioxx, these incidents put the Pharma industry firmly in the dock. In fact, there have been several reports that all is not well with clinical trials, that aim to develop new therapeutic or preventive measures, assess or evaluate an existing medical treatments and techniques vis-à-vis a new one.
As a series of incidences of unfortunate events associated with clinical trials came to light, there has been a growing call for transparency, accountability and accessibility of clinical trials and their results in order to re-establish public trust in clinical trial data. All these appear to be possible only by



Mandatory registration of all clinical trials, with the ultimate goal of ensuring that all trial results, positive or negative will be released to the public. Several trial registries are already in place the world over, such as the ACTR, ClinicalTrials.gov, ISCRTN, etc. Furthermore the WHO is promoting an international initiative to develop a Meta register of controlled trials that would offer a one step search portal fed from existing registers and provide a unique identification number for clinical trials from certified registers that needs standard criteria for the exchange of essential trial data. Keeping with the times and its demands, a registry, Clinical Trial Registry-India (CTRI), funded jointly by DST, WHO and ICMR has been initiated. The CTRI has been set up at NIMS (ICMR), New Delhi to provide a platform for registration of all clinical trials in India. Primary objectives are to establish public record system by registering all prospective clinical trials conducted in India on health products including drugs, devices, vaccines and herbal drugs which will made publicly available on the internet at no cost.

National pharmacovigilance programme:
The government of India, with the World Bank, has initiated the National Pharmacovigilance Programme. The Central Drugs Standard Control Organization (CDSCO) is coordinating the country wide pharmacovigilance programme under the aegis of DGHS, Ministry of Health and Family Welfare, New Delhi. With the number of new drugs being regularly approved for marketing in India, there is a need for a vibrant pharmacovigilance system in the country to protect our population from the potential harms that may be caused by some of these new drugs. Besides, with the patent regime coming in force from 2005, it is widely believed that India would become the global hub for new drug trials. These situations make it pertinent for the Indian central drugs regulatory authority to have a vibrant pharmacovigilance system in the country.









The Regulatory Approval process:
Clinical trials are now regulated by the Drugs Controller General of India (DCGI), whos is responsible for assuring that all clinical trials comply with the requirements of the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, as well as Good Clinical Practices. The DCGI approval process categorizes clinical trials into two types. If the study protocol has already been approved by a recognized regulatory authority in more or more developed countries (such as the U.S., Canada, U.K., Switzerland, Germany, Australia, Japan, and South Africa), the study is classified as a Type A trial and can be approved using a fast track process within two to six weeks after the required documentation has been submitted. All other studies are classified as Type B, for these, the approval process is generally 8 to 12 weeks. The Institutional Review Board (IRB) approval process can be conducted in parallel with the DCGI review and, if import licenses are needed, the applications for these can also proceed in parallel. These provisions facilitate the process of getting study protocols in place and quickly initiating the trials.



Bridging the Needs:
Western Pharma companies need to increase productivity, decrease costs, and shorten the time to market for new drugs. One solution is conducting clinical trials that provide lower cost and faster recruitment without compromising the quality of the research. India clearly offers this solution. In the past, several constraints have limited the number of clinical trials conducted in India:
• Communication can be an issue because of cultural differences between Western countries and India.
• The difference in time zones creates further difficulties in communication and monitoring of work.
• There are some significant differences between Western and Indian business cultures.
• Indian researchers need to clearly understand the requirements of Western pharmaceutical companies and their regulatory requirements.
• Western companies need to overcome their perception of India as a non-traditional “developing” nation that is the “land of the generics” with limited capacity and uncertain quality of work.
These issues are not unique to clinical trails. Similar issues have been faces and successfully addressed in fields such as information technology (IT) and business process outsourcing (BPO), where India is now a leading provider of services to western clients.











Barriers:
The overall time and cost advantage in bringing a drug to market by leveraging India’s resources could be as high as US $200 million, hence the steadily increasing number of global studies in India over the past two years. Major pharmaceutical companies estimate the total market for conducting clinical trials either directly or through contract research organizations (CROs) in India through 2010 at US $ 2billion. CROs themselves are fast gaining importance because of their global presence, specialized local expertise, and competitive pricing strategies. And a significant number of new CROs have set up operations in India over the past two years.

However, some key barriers stand in the way of opportunities, including patients’ rights and safety, regulatory framework, infrastructure, organization of ethics committees, data quality, lack of training curricula focusing on clinical research, and other factors. Most of these barriers are common to all developing countries and need to be addressed in a similar way.

Patients’ Rights and safety:
The drug development process requires 10 to 12 years on average to reach the marketing approval stage. Participation in clinical trials provides an opportunity to experience the benefits of these new drugs. So a critically ill patient who participates in a clinical trial, and who may not be alive after eight to 10 years when the drug would be made available in the market, has access to what may provide either longer term health benefits or an improved quality of life. By carefully evaluating the eligibility criteria, a clinical investigator can offer new hope to patients across a wide range of therapeutic areas.

Participation in clinical trials also provides research professionals opportunities to offer the best care to patients. A well-designed and executed study has built-in provisions to ensure patient rights and safety. In fact, a patient may be far safer in a clinical trial then in routine medical care because careful


observations are made on safety (toxicity) and efficacy. In addition, clinical trials move in phases, that is, phase II trials are initiated only if the phase I results are promising. Similarly, phase III trials are conducted only if the drug has shown required safety and efficacy in early phase trials. Hence, a patient is at minimized risk during later phases of clinical trials. This phase process is particularly important in developing countries if carefully understood and explained to potential subjects.

Regulatory Framework:
Multinational pharmaceutical companies and CROs are able to conduct good quality clinical trials in India despite infrastructural challenges at the regulatory departmental level. They can do so because of required professional training and the professional’s willingness to comply with regulations and applicable standards in a spirit that protects the rights and safety of trial subjects. In India, no less than in the rest of the world, it is the responsibility of individual stakeholders (sponsors, CROs, investigators) to observe self-discipline while conducting clinical trials, especially when there are more than 20,000 big and small companies and a mere handful of regulatory professionals.

The belief that compliance with Good Clinical Practices (GCP) and applicable regulatory guidelines requires the presence of a robust regulatory inspection system is erroneous. Rather, what may be required is a change of mindset from one of “situational ethics” (that is, compliance with medical ethics in clinical trials only) to one of “holistic ethics” (that is, compliance with medical ethics in clinical trials as well as routine medical care). No regulatory authority can ensure 100% GCP compliance unless the individual stakeholders are willing to comply with the applicable regulations.









Conduct of illegal/unethical Trials:
Scientific misconduct is a global phenomenon linked to human behavior rather than to an individual country. For instance, the U.S. Food and Drug Administration (FDA) website lists the details of clinical investigators who have been “disqualified” or “restricted” from doing research on grounds of scientific misconduct. Details of warning letters issued to various stakeholders (clinical investigator, ERB/IRB, sponsor, CRO, etc.) can also be obtained from the same website. However, FDA has not banned clinical trials based on these grounds, these individuals, or individual organizations. Rather, FDA has increased its surveillance over clinical research programs. In like manner, the Indian regulatory authority is also in the process of setting up surveillance teams for ensuring ethical conduct of clinical trials.
Companies acting ethically set globally consistent standards and conduct trials only in the countries where GCP compliance is assured. Indian investigators have demonstrated their compliance by virtue of participation in more than 60 global trials so far. Moreover, a majority of those trials were FDA or European registration trials, requiring strict compliance with GCP and regulatory guidelines. The data have been accepted by foreign regulatory authorities and published in international scientific journals of repute.

Infrastructure:
Participation in global clinical trials requires an upgrade in existing infrastructure and facilities at a majority of Indian hospitals in terms of functioning of ERB/IRB, calibration and quality control of diagnostic equipments, maintenance of patient medical records, handling of investigational product, and other critical areas.
There have been instances of sponsors providing highly expensive diagnostic instruments to trial sites in order to achieve consistency in trial data globally. All the trials include investigator grants and funding that is generally utilized to upgrade the infrastructure and education facilities at a site. The Institutional Ethics Committees at a majority of Indian hospitals are gaining competence in evaluating


the trial proposals from scientific and ethical standpoints. This, in turn, is strengthening the healthcare system of the country while bolstering the ability of institutions to conduct research. In short, clinical research offers value-added infrastructural incentives to the country.

Functioning of ethics committees:
According to a survey conducted by ICMR, ECs are functioning in over 200 institutions. However, there is no accreditation of ECs. Besides, some ECs have an irregular schedule of meetings, lack standard operating procedures, and do not have a composition in line with GCP guidelines. The ICMR has planned to review and audit the functioning of ECs and to introduce a national accreditation system for them. Additionally, the ICMR has also established an Independent Forum for Ethics Review Committees, which will organize training programs for the members of ECs. The revised schedule Y of Drugs and Cosmetic Rules devotes significant attention to the roles and responsibilities of ECs, prescribes the composition of ECs as per the ICMR guidelines and provides formats for the approval letter of ECs. These government initiatives are likely to improve the current situation.

Responsibilities of investigators:
In 2002, there were 200-250 GCP trained investigators and 40-50 GCP clinical studies were conducted. These small numbers imply that many potential clinical investigators do not have the experience of conducting GCP trials. Though this is not considered negative, it does require a major investment in training during study start-up. For the investigators struggling to balance patient care and research activities, compliance to GCP is an additional new responsibility. In addition, low literacy levels and poverty amongst the patients and the pressure of quick patient recruitment from the sponsors pose significant challenges to an investigator making efforts to obtain proper informed consent from the patients. The stress on documentation of the informed consent process in the GCP training programs, and the adverse media publicity to several recent clinical trial mishaps and subsequent government enquires have increased the awareness amongst the investigators about ethical and regulatory issues and the need for adequate patient protection.



Training:
Lack of technical know-how on drug development and the habit of “copying” (mostly producing generic drugs) are the major hurdles for indigenous drug research. Participation in global trials provides learning opportunities to Indian doctors and scientists, which in turn can be utilized to find the answers for the diseases that are endemic to the country, such as kala-azar, leprosy, trachoma, and tuberculosis. The medical research intellectual base of the country has been Sub optimally utilized so far due to the absence of basic research facilities and knows how.

Participation of Indian investigators in global trials and subsequent publication/presentation motivate them to develop research protocols for domestic health care issues. This, in turn, is nurturing a culture of medical research that can match international standards.

Pricing:
Less than 10% by value of drugs used in India are of the premium category; the other 90% are established off-patent drugs (drugs for which multiple generic versions are available). Even for premium category drugs, the pricing is generally moderated by three important factors:
 The purchasing power of the customers;
 The existence of unpatented drugs and cheaper substitutes; and
 The Drug Price Control Order, which regulates the pricing of essential life-saving drugs in India.
Even today, people who can afford the premium category drugs are getting them imported from the west or are traveling to other countries to get better medical care. The availability of such drugs in India is going to reduce the overall healthcare cost.








CASE STUDY:

Indian Guinea Pigs for Sale: Outsourcing Clinical Trials
This article was shown different perspective what type of unethical clinical trial business occurred in India
1) Two Indian pharmaceutical companies conducted trials of genetically engineered drugs without proper approvals, have renewed fears about unethical drug research in India. This case involved Bangalore-based Biocon and Hyderabad-based Shantha. Biotech conducted Phase III trials of genetically engineered drugs (insulin for diabetes by Biocon and streptokinase for heart attacks by Shantha) without appropriate prior approval of both the Drug Controller General of India (DGCI) and the Genetic Engineering Approval Committee. Press report was said that approval letter DCGI got or not. Also both companies applied to the GEAC only after the trials started.
Result of this study: Some people died in the Shantha trial, conducted on seriously ill patients. This study was conducted in 2003.Company does not followed Indian GCP regulation and ICH-guideline when recruiting patients in trial. In emergency situation company does not obtained proper informed consent process. Also company did not provide compensation to trial related injury.
2) Mumbai-based Sun Pharmaceutical Industries Limited bypassed the DCGI altogether and got private doctors to prescribe the anti-cancer drug Letrozole to more than 400 women for ovulation induction. They used the results to promote this drug through medical representatives for this unapproved usage. While there are debates about doctors' legal and ethical right to prescribe a drug off-label, off-label research done without following proper procedure is outright illegal. Letrozole is patented by Novartis. There is nothing to indicate that Novartis was involved in the illegal trial.




Conclusion:
Although it typically takes 10 to 12 years and millions of dollars to bring one new drug to market, the success rate is small. In the developing world, no company or institute wants to, or can, invest such time and resources for a marginal improvement in responses over existing therapies. Fortunately, in a majority of cases, clinical trials can provide answers regarding the use or not of a therapeutic agent that can benefit millions of patients worldwide. Being the second most populated country in the world, India can contribute significantly to global development programs.
The evolution of GCP in the west- from the Nuremberg Trials till the development of ICH-GCP guidelines-took almost five decades. India’s involvement in global GCP trials is only about a decade old. ICMR’s Ethical Guidelines for Biomedical Research on Human Subjects were launched in 2000 and Indian GCP guidelines became available in Dec 2001. The experience of conducting global GCP trials limited. GCP is a shared responsibility amongst sponsors, investigators, regulators and ethics committees. As all stakeholders are still learning, the journey towards achieving global quality is unlikely to be smooth. The efforts of the government and industry to create awareness through GCP workshops and to provide training to the investigators and ECs will go a long way in creating a culture of global GCP quality trials.
The foundation of knowledge -based industries in India was laid down by the information technology industry, and there is no reason why clinical research cannot follow in those footsteps. Indian investigators and clinical research professionals have already demonstrated their medical and scientific skills by participating in multiple global clinical trials. It is time now to move forward to capitalize on the opportunity.








BIBILOGRAPHY:-
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2. “Clinical Research in India” by Dr Swapneel Anaokar in Pharambiz.The author is Head - Clinical Research and Regulatory Affairs, GlaxoSmithKline Pharmaceutical Limited, India Tuesday, February 12, 2002 11:16 IST
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ADVANCES IN CHEMOTHERAPY FOR LEUKEMIA

Sruman Bandaru.
B.Pharm.
#2-10-711, Teachers Colony
Phase –I, Subedari,
Hanamkonda
Dist: Warangal
State: Andhra Pradesh,
India, PIN - 506370
E-mail: sruman.bandaru@gmail.com

Dr.P.Nanda Kishore.
MD.Fellowship (U.K)
Oncologist and clinical hematologist
Director of Life Line Hospitals
Hanamkonda
Dist: Warangal
State: Andra Pradesh
India.

Abstract:
The article focuses on four major types of leukemia along with their etiopathogenesis, treatment, chemotherapy, with different combinations, recent advances in chemotherapy, future directions for better understanding the disease and to research different combination of drugs so has to improve the survival rate of leukemia patients.

INTRODUCTION:
Lukemia is cancer of blood characterised by an uncontrolled proliferation of blood forming cells in the bone marrow.
There are four major types of leukemia
a) Acute myelogenous leukemia(AML)
b) Chronic myelogenous leukemia(CML)
c) Acute lympho blastic leukemial(ALL)
d) Chronic lymphocytic leukemai(CLL)
(Note: myleogenous and lymphocytic refer to the type of cell affected.).

ETIOPATHOGENESIS OF LEUKEMIA:
Acute leukemia progresses much more rapidly than the chronic disease. In acute leukemia genetic mutations in the blood forming cells result in a excesses of immature blood cells in the bone marrow and blood, essentially at the cost of the production of healthy marrow cells. As a result, the marrow cannot produce enough red blood cells, white blood cells and blood platelets, leaving individuals anemic, susceptable to infection and bleeding diathesis.in chronic lukemia greater number of more mature cells are produced.
ALL and aml are marked by the accumulation of immature cells called blasts, which fail to function as normal blood cells.
Cll is charcetrised by an overproduction mature lymphiod cells
Cml (and some cases of ALL) is caused by a genetic anamoly in the blood –forming cells known as translocation, in which part of one chromosome breaks off and attaches to another chromosome. In this case a section of chromosome 9 tears away and connects onto a section of chromosome 22,resulting in the fusion of two genes BCR and ABL, which are normally separate.
The new BCR-ABL gene produces an abnormal enzyme that results in the uncontrolled growth of white blood cells, i.e, blood cancer.



ACUTE MYELOID LUKEMIA:
Acute myeloid leukemia (AML) is an aggressive cancer of the white blood cells the cancerous white blood cells or blasts are abnormal, immature white blood cells, which occupy the bon emarrow and replace the normal components involved in the formation of normal blood cells. Because of this, the normal white cells, red cells and platelets are decreased, this leads to symptoms of anaemia (weakness, shortness of breath on exerction etc), infections and bleeding or symptoms of stroke or hearts disease.
Aml is more common in older adults.while this disease occurs in less than 1/1 lac individuals less than 30 years of age, the frequncy is greater than 11 /1 lac individuals more than 30 years of age.

TREATMENT:
Conventional treatment of AML consists of chemotherapy-a combination of medications usually given through vein or more commonly a “catheter” that is placed in the chest. Most chemotherapy regimes consists of combination of drugs “cytosine arabinoside”(Ara-c (or) cytarabine) and one of the drugs in the family of “anthracyclines.”(Daunorubicin, Idorubicin, Mitoxantron etc). In the recent years, various combination therapies have achieved remission rates of nearly 80% in young-adult patients with AML. Though there are patients who achieve remission, still 60% eventually experiencing a relapse of this disease.
Stem cell transplantation (or bone marrow transplantation) offers the opportunity to treat leukemia with the back up of high doses of chemotherapy or combinations of chemotherapy and radiotherapy.
The goal of high dose chemotherapy or radiotherapy before transplantation is to permanently kill the leukemia cell population. Transplanted stem cells from a matched donor provide the seeds to replenish the normal blood cells.

RECENT ADVANCES:
The following are some of the recent advances in the treatment of AML:

(a) Monoclonal antibodies are proteins that target specific markers on the tumor cells and destroy them. These agents have the advantage of sparing the normal cells and therefore have fewer side effects like hair loss or damage to the heart, which may be seen with chemotherapy.
A monoclonal antibody is now available against the CD33 antigen that is located on the surface of the most AML cells. The FDA has approved the drug mylotarg, which is a combination of this antibody with a very toxic agent called calichamycin. When the antibody attaches to the CD33 marker,the calichamycin is released in the cell and destroys it combination of chemotherapy with mylotarg is being tried as an investigational treatment in many centers in united states and other countries.

(b) A new drug called clofarabine is being a tried in-patient with AML at selected institutions in USA in clinical clinic. This drug is given intravenously in the out patient clinic. This drug is tolerated by patients well and is showing a lot of promise in the treatment of AML. Another drug i.e being tried is 5-azacytidine that was recently shown to significantly benefit patients with pre-leukemia. Troxacitabine is yet another investigational chemotherapy agent, which is being tested for the treatment of AML.

(c) In-patients, who are eligible for bone marrow or stem cell transplantation, newer modalities of therapy include “Mini” transplants or “non-myeloblative stem cell transplantation”. These modalities utilize less intensive “conditioning” therapy prior to transplantaion. Because of less intensive therapy, this procedure may be tolerated better than conventional transplantaion, particularly by patients who are near the upper age limits for transplantation.








Future prospects of AML:
A myriad of new agent is now available which, when administered either alone (ATRA or arsenic trioxide in APL) or in combinations with each other or with conventional cytotoxic chemotherapy, have the potential to reduce the disease patients with AML. Combinations of several agents targetting, more than one gene mutation, signal transduction pathway or antigenic determinant may be the most effective.
The challenge will be to detemine the specific pathway responsible for the propagation of the leukemia cells from a specific clone. This can be achieved with correct strategy and combinations of different agents.

CHRONIC MYELOID LEUKEMIA:
Chronic Myeloid Leukemia (Chronic myelogenous leukemia, CML) is a disease characterized by increased WBC, anemia and enlarged spleen. The disease usually occurs in older persons but may occur at any age. The patient may complain with symptoms of anemia (pallor, fatigue or tiredness) or that of enlarged spleen (fullness of abdomen, early satiety or abdominal discomfort) or the diagnosis may result from the investigation of an incidental finding of a big spleen. The presence of Philadelphia (ph’) chromosome in the leukemic cells in the blood or bone marrow.

TREATMENT:
The only known “curative” procedure for CML is the stem cell transplantation from a matched donor. The results of this treatment are best in the chronic phase especially if it is done in the first year after diagnosis. Out side this various treatment options are available with drugs like vinorelbine tartrate (navelbine), Imatinib mesylate (Gilvec), samarium-153, ethylene diaminetetramethylene phosphate (EDTMP), Temazepam (euhypnos).
Interferon alfa is a drug that is very effective in the chronic phase of CML. However, more than half of the patients has significant side effects from the drug.
Imatinib mesylate (Gleevec) has revelutionized the therapy of CML. There is evidence that this drug is superior to other conventonal therapy options in CML including Interferon-alfa, with significantly less toxicity.

FUTURE PROSPECTUS:
Although much has been achieved, many important issues pertaning to the biology and treatment of CML remain unresolved. To mention just a few, we know little of the mechanisms that cause the chromosomal rearrgement. We still need to clarify how deregulation of signal transduction by the BCR-ABL oncoprotien leads to the proliferative advantage of the ph-positive clone. We need to have a much better understanding of the molecular basis of disease progression, which is of tremendous value. In therapeutic terms we need to define the true clinical potential of imatinib and to acertain whether combining this agent with other signal-transduction inhibitors, other cytotoxic drugs or differntiating agents can improve its efficacy. We need to know whether immunizing patients with CML can prolong their survival or contribute to the eradication of disease. It seems that atleast some of these problems will be solved within the next five years.

ACUTE LYMPHOBLASTIC LEUKEMIA:
Acute lymphoblastic leukemia (ALL) is a fast-growing cancer of the white blood cells. Lymphocytes are a type of white blood cell, which fight the infections. In ALL, the bone marrow makes lots of unformed cells called blasts that normally develop into lymphocytes. However, the blasts are abnormal. They do not develop and cannot fight infections. The number of abnormal cells (or leukemia cells) grows quickly. They crowd out the normal red blood cells, white blood cells and platelets the body needs.
It appears most often in childern younger than 10 years of age. ALL is the most common leukemia in children. However, it can appear in people of any age. About one third of cases are adults. ALL may also be called acute lymphoid leukemia.





Signs and symptoms:
(a) Reduced red blood cells, which lead to anemia-feeling tiredness or weak, with shortness of breath and looking pale.
(b) Reduced number of white blood cells, which lead to fever and frequent infections that are difficult to treat.
(c) Reduced platelets which leads to easy brusing or bleeding and tiny red spots under the skin(petechiae)
(d) Increased leukemic cells cause pain in the joints, lack of appetite, headache or vomitting. These symptoms are less common.

Treatment:
Chemotherapy for acute lymphoblastic leukemia:
There are 3 phases of chemotherapy treatment for ALL: induction, consolidation and maintenance. Many patients also receive treatment called intrathecal chemotherapy to prevent leukemia from spreading to the central nervous system.

Induction chemotherapy:
Most patients with ALL are given induction chemotherapy. The goal of induction therapy is to bring the disease into remission. Remission is when the patient’s blood counts return to normal and bone marrow samples show no signs of disease. Induction therapy achieves a remission in more than 95% of childern and is about 75% to 89% of adults. Induction therapy is usually very intense and lasts about one month.

Consolidation therapy:
Consolidation therapy, the second phase of chemotherapy is also intense, it lasts about 4 to 8 months. The goal of consolidation therapy is to reduce the number of disease cells left in the body. The drugs and doses used during consolidation therapy depend on the patient’s risk factors.

Maintenance thearpy:
If a patient stays in remission after induction and consolidation therapy, maintenance therapy begins. The goal is to destroy disease cells that remain so that the leukemia is completely gone. Maintenance therapy is less intense than the other two phases. It may last two or three years.

Intrathecal chemotherapy:
During all three phases of chemotherapy treatment, many patients receive extra chemotherapy to destroy leukemia cells that may have spread to the central nervous system (the brain and spinal cord). This chemotherapy is injected right into the spinal fluid using a lumber punture (spinal tap) or an omaya reservoir (a device placed under the scalp). It is called intrathecal chemotherapy.

Bone marrow or cord blood transplant for acute lymphoblastic leukemia:
For some patients a bone marrow or cord blood transplant may offer the best chance for a long-term remission. A transplant is a strong treatment with risks of side effects, so it is not used for all patients with ALL. Transplant are used when chemotherapy alone is unlikely to provide a long-term remission.

Allogenic transplants for ALL:
The most suitable transplants for ALL are allogenic. An allogenic transplant from a family member, unrelated donor or cord blood unit replaces the abnormal cells in the patients bone marrow with healthy blood-forming cells Patients may receive an allogenic transplant in first remission, in second or third remission. It can also be employed after a relapse or while the disease is active if they do not reach remission.






Autologous transplants for ALL:
Another option for some patients may be an autologous transplant, which uses the patients own blood-forming cells. Autologous transplants have risks of serious side effects, but these risks are lower than allogenic transplants. However, patients have a higher risk of relapse of this leukemia after autologous transplants. This is because leukemia cells may retrun to the patient along with his or her blood forming cells.
Drugs used: fludarabine phosphate (fludara).

CHRONIC LYMPHOCYTIC LEUKEMIA:
Chronic lymphocytic leukemia as CLL in short, is a type of leukemia in which too many lymphocytes are produced. Although the malignant lymphocytes in CLL may look normal and mature, these cells may not cope effectively with infection.
CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, the risk factor is aging over 50 years. More then 7,000 new cases of CLL are diagnosed in the U.S each year.
Patients with CLL show the symptoms such as lymphnodes, most commonly in the cervical (neck) area. Other symptoms, patients complain are the so-called “B symptoms” of lymphoma that include weight loss, fever, night sweats and extreme fatigue.

Treatment:
While it is generally considered that CLL is incurable it progresses slowly in most cases. Many people with CLL lead normal and active life for many years in some cases for decades. Because of slow onset, early stage CLL is generally not treated. Since it is believed that early intervention does not imporve survival time or quality of life, the condition is monitored over time.
The decision to start CLL treatment is taken when the patient’s clinical symptoms or blood counts indcate that the disease has progressed to a point where it may affect the patient’s quality of life. Clinical “staging sytems” such as the Rai4-stage system and the Binet classification can help to determine when and how to treat the patient.
CLL treatment focuses on controlling the disease and its symptoms rather then on an outright cure. Chemotherapy, radiation therapy, and biological therapy or bone marrow transplantation are used to treat CLL. Symptoms are some times treated surgically (splenotomy: removal of enlarged spleen) or by radiation therapy (“de-bulking” of swollen lymph nodes). Intial CLL treatments vary depending on the exact diagnosis and the progression of the disease and even with the preference and experience of health care practitioner. There are dozens of agents used in the treatment of CLL, and there is considerable research activity studying them individually or in combination with each other. For example, although the purine analogue fludarabine was shown to give superior response rates than chlorambucil as primary therapy, there is no evedence that early use of fludarabine improves over all survival, and some clinicians prefer to reserve fludarabine for relapsed disease. Combination chemistry regimens such as fludarabine with cyclophosphamide, FCR (fludarabine, cyclophosphamide and rituximab) and CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) are effective in both newly diagnosed and relapsed CLL. Allogenic bone marrow (stem cell) transplantation is rarely used as first line treatment for CLL due to its risk.
“Refractory” CLL is the CLL no longer responds favourably to treatment. In this case more aggressive therapies, including bone marrow (stem cell) transplantation, are considered. The monoclonal antibody, alemtuzumab (directed against CD52) may be used in-patients with refractory and bone marrow based disease. There is increasing intrest in the use of reduced intensity allogenic stem cell transplantation, which offers prospect of cure for selected patients with a suitable donor.








CONCLUSION:

Survival of patients with leukemia has improved dramatically over the years. From 1960 to 1963, an individual with leukemia, had a 14% chnace of living five years, by 1995 to 2000 the number had jumped to 46%.
Leukemia in gendral is 10 times more common in adults then in children, with the noteable exception of ALL, which accounts for approximately 78% among children. AML and CLL are the most common adult leukemia (approx.10, 980 and approximately 8,900 expected cases, respectively in 2005). The incidence of AML, CLL and CML increases drastically after age of 40 and is highest in those 60 years of age and older. The statistics regarding how long individuals live with leukemia vary according to the type of disease. Only about 20% of those with AML live for five years (approx) where as 70% of individuals who have CLL live that long. Survival numbers have raisen dramatically for those with ALL in the past several decades, largely due to advances in therapies for childeren. In the 1970’s, the five-year relative survival rate was 38%. By the late 90’s, it had reached 65%. In children with ALL, the survival rate in that period went from 53% to 85%. The vast majority of cases of CML occur in adults, and its frequency esculates with age. It is estimated that only one in one millon children upto age 10 develops CML, rising to one in 100,000 by age 50 and to one in 10,000 by age 80. The five-year survival rate between 1995 and 2000 was approxmately 37%.

REFERENCES:
1) Leukemia Research Foundation website, www.leukemia-research.org

2) Margolin JF, steuber CP, poplack DG. Acute lymphoblastic leukemia. In: pizzo PA, poplack DG, Eds. Principles and practice of pediatric oncology. 4thed. Philadelphia: Lippincott Williams & Wilkins; 2002: 489-544

3) Gokbuget N, Hoelzer D. Recent approaches in acute lymphoblastic leukemia in adults. Rev clin Exp Hematal. 2002; 6(2): 114-141.

4) Pui C-H, Relling MV, Dowing JR. Acute Lymphoblastic Leukemia N Engl J Med.2004; 350(15): 1535-1548.

5) Rai KR, peterson BL, Appelbaum FR, kolitzj, Elias L, shepherd L, Hines J, Threatte GA, Larson RA, cheson BD, schiffer CA (2000). “Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia.” N Engl J Med 343(24): 1750-7.

6) Keating MJ, Flinn I, Jain v, Binet JL, Hillmen P, Byrd J, Albitar M, Brettman L, santabarbara P, Wacker B, Rai KR (2002). “Therapeutic role of alemtuzumab (campath-1H) in patients who have failed fludarabine: results of a large international study.” Blood 99(10): 3554-61.

7) Dreger P, Brand R, Hanszj, Milligan D, Corradini P, Finkej, Deliliers GL, Martino R, Russell N, VanBiezen A, Michallet M, Niederwieser D; Chronic Leukemia working party of the EBMT (2003). “Treatment-related mortality and graft-versus –leukemia activity after allogenic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning”. Leukemia 17(5): 841-8. PMID 127.

8) Semin Hematol. 2002 Oct; 39 (4 suppl 3); 1-5.

9) Curr Opin Hematol. 1999 Jul; 6(4): 222-8.

10) Int J Hematol. 2002 Aug; 76 suppl 1: 250-2’




11) Berman E: Chemotherapy in acute myelogenous leukemia: high dose, higher expectations? J clin oncol 1995, 13: 1-4.

12) Mayer RJ, Davis RB, schiffer CA, etal.: Intensive postre mission chemotherapy in adults with acute myeloid leukemia. N Engl J med 1994, 331: 896-903.

13) Imire K, Dicke KA, Keating A: Autologous bone marrow transplantation for acute myeloid leukemia. Stem cells 1996, 14: 69-78.

14) Mitus JM, Miller KB, Schenkein DP, and etal: Improved survival for patients with acute myelogenous leukemia. J clin oncol 1995, 13: 560-569.

15) Geary CG.The story of chronic myeloid leukemia.BrJ Haematol 2000; 110:2-11.

16) Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia science 1960; 132:1497.

17) Sawyers CL. Chronic myeloid leukemia. N Engl Med 1999; 340: 1330-40.

18) Eaver CJ,Eaves AC.Stem cell kinetics.BillieresClin Haematol 1997;10: 233-57.

19) Deininger MW, Goldman JM, melo JV. The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343-56.

20) Verfaillie CM.Chronic myelogenous leukemia: from pathogenesis to therapy. J Hematother 1999; 8: 3-13.

21) Estey E. Hematopoietic growth factors in the treatment of acute leukemia. Current Opinion in oncology 10(1): 23-30, 1998 Jan.

22) Thomas X, Archimbaud E: Mitoxantrone in the treatment of acute myelogenous leukemia: A review Hematology & cell therapy 39(4): 63-74, 1997 Aug.

23) Bishop JF: The treatment of adult acute myeloid leukemia seminars in oncology 24(1): 57-69, 1997 Feb.


















July 17, 2007 | 10:30 AM Comments  0 comments
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DENGUE
Related to country: India

WEST LAFAYETTE, Ind. – High-quality images of a virus still forming in its cellular host shed light on how viruses reproduce, knowledge that could prove important to the development of antiviral drugs.

immature dengue particle
Download photo - caption below

A team including Purdue University's Michael Rossmann and Richard Kuhn has solved the structure of the immature dengue virus, which is related to West Nile virus and yellow fever. Dengue is a mosquito-borne pathogen that kills more than 24,000 people in the world annually. The pair solved the structure of the mature dengue virus particle last year (see related story), and Rossmann said the new findings were a significant step toward unraveling the behavior of viruses.

"We're beginning to dissect the individual steps in a virus' life cycle," said Rossmann, who is Henley Distinguished Professor of Biological Sciences in Purdue's School of Science. "We hope to learn a great deal more about viral development so that approaches to preventing infection become conceivable."

mature dengue particle
Download photo - caption below

The study, a collaboration among Rossmann, Kuhn and Tim Baker at Purdue and James Straus at the California Institute of Technology, appears in the June 2 issue of EMBO.

The research group used an advanced imaging technique, known as cryoelectron microscopy, to take 3-D pictures of the dengue particle – the term experts use to denote a single virus. While viruses are not considered to be "alive" by the standards we apply to plants and animals, the team's images have revealed that particles go through a complex developmental process.

"We have discovered that an astonishing structural change occurs between the immature and mature dengue shells," said Kuhn, also professor of biology. "We don't yet know how it all happens – but even though we have only seen two points along the viral assembly line so far, we can tell it's quite a dynamic metamorphosis."

Compared to the mature dengue particle, for example, the immature form is 15 percent greater in diameter.

"The immature particle is covered with 60 three-pronged protein spikes, called trimers, that jut from its surface," Kuhn said. "In contrast, the mature particle is a nearly smooth sphere, like a golf ball. Somewhere in the assembly process, these trimers flatten out, making the surface appear more even."

The proteins are important because each contains a short amino acid sequence called a fusion peptide that the virus needs to attach itself to a potential host. Without this fusion peptide, the virus cannot successfully invade a cell.

"If you compare a virus to a pirate ship, these peptides are the grappling hooks by which they attach themselves to their prey," Kuhn said. "A particle can only inject its genetic material into a cell after it has bonded with its surface. Fusion peptides allow the virus to prepare for boarding, so to speak."

The peptides need to be protected until the virus is ready to bond with a cell, so in the immature particle, each peptide is covered with a special cap that protects it until the time is right.

"We would like to know more about how a virus changes," Rossmann said. "Our imaging techniques are now giving us vastly greater perspective on how a particle becomes a successful invader. Now we want to know how it marshals its offenses and defenses."

It is in examining the changes a virus undergoes– for example, in the case of dengue, how it uncaps its fusion peptides to become an infectious agent – that the team hopes to find clues to stopping the developmental process in its tracks.

"Any knowledge of the steps in a virus' assembly process provides a potential target for an antiviral agent," Rossmann said. "If you are trying to assemble something, introducing a foreign body into the process could gum up the works."

But Kuhn said much more work needs to be done before such medicines will appear in your drugstore, as the full picture of viral assembly remains unclear.

"This is only one step in the viral maturation process," Kuhn said. "We still need other scenes from its cycle of existence – snapshots of it fusing with a cell, for example, and of it entering – to have complete understanding."

The team's next step will be to confirm its findings, which Kuhn considers critical. The metamorphosis the dengue particle undergoes is so radical, he said, that there is a possibility the immature form the team has seen is not actually a step in dengue's development. For the moment, however, the results are encouraging enough to pursue the research further.

"Knowledge of how a virus assembles itself can reveal its vulnerabilities," Kuhn said. "This is what our research techniques allow us to explore – and perhaps exploit."

This research was funded in part by the Allergy and Infectious Diseases Institute at the National Institutes of Health.

Rossmann and Kuhn are associated with Purdue's Markey Center for Structural Biology, which consists of laboratories that use a combination of cryoelectron microscopy, crystallography and molecular biology to elucidate the processes of viral entry, replication and pathogenesis.

October 23, 2006 | 3:10 AM Comments  0 comments
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HOW TO START A GMP COMPLIANCE ORGANIZATION?
Related to country: India

GMP COMPLIANT ORGANIZATION: HOW TO START?


Sruman Bandaru
#2-10-711, Teachers Colony
Phase-1, subedari,
Hanamkonda
Dist: Warangal
State: Andhra Pradesh,
India, PIN-506370
E-mail: sruman_bandaru@yahoo.com

Introduction:
WHO defines Good manufacturing practices (GMP) as “that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.”
Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:
i. All manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications:
ii. Critical steps of manufacturing processes and significant changes to the process are validated;
iii. All necessary facilities for GMP are provided including;
a) Appropriately qualified and trained personnel;
b) Adequate premises and space;
c) Suitable equipment and services;
d) Correct materials, containers, and labels;
e) Approved procedures and instructions;
f) Suitable storage and transport;

iv. Instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;



v. Operators are trained to carry out procedures correctly;

vi. Records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated;

vii. Records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

viii. The distribution (wholesaling) of the products minimized any risk to their quality;

ix. A system is available to recall any batch of product, from sale or supply;

x. Complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent re-occurrence.

PREMISES
Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimise the risk of errors and permit effective cleaning and maintenance in order to avoid cross-contamination, build up of dust or dirt and, in general, any adverse effect on the quality.
i. Premises should be situated in an environment which, when considered together with measures to protect the manufacture, presents minimal risk of causing contamination of materials or products.
ii. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned, and where applicable, disinfected according to detailed written procedures.
iii. Lighting, temperature, humidity, and ventilation should be appropriate and such that they do not adversely affect, directly,or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment.
iv. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals.
v. Steps should be taken in order to prevent the entry of unauthorized people. Personnel who do not work in them should not use production, storage and quality control areas as a right of way.






STORAGE AREAS:
1) Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products starting and packaging materials, intermidate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.
2) Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (eg.temperature, humidity) these should be provided, checked, and monitored.
3) Receiving and dispatch bays should protect materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.
4) Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. Any system replacing the physical quarantine should give equivalent security.
5) There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination of cross-contamination.
6) Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.
7) Highly active materials or products should be stored in safe and secure areas.
8) Printed packing materials are considered critical to the conformity of the medicinal products and special attention should be paid to the safe and secure storage of these materials.

PRODUCTION AREA:
i. In order to minimise the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (eg.penicillins) or biological preparations (e.g. from live micro-organisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxins, certain highly active drugs and non-medicinal products should not be conducted in the same facilities. For those products, in exceptional cases, the principle of campaign working the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. The manufacture of technical poisons, such as pesticides and herbicides, should not be allowed in premises used for the manufacture of medicinal products.
ii. Premises should preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.
iii. The adequacy of the working and in-process storage place should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.
iv. Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free



From cracks and open joints, and should not shed particulate matter and should permit easy
And effective cleaning and, if necessary, disinfection.
v. Pipe work, light fittings, ventilations points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.
vi. Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.
vii. Production areas should be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment.
viii. Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.
ix. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.
x. Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.
xi. Production areas should be well lit, particularly where visual on-line controls are carried out.
xii. In-process controls may be carried out within the production area provided they do not carry risk for the production.

EQUIPMENT:

i. Manufacturing equipment should be designed, located and maintained to suit its intended
Purpose.
ii. Repair and maintenance operations should not present any hazard to the quality of the
Products.
iii. Manufacturing equipment should be designed so that it can be easily and thoroughly
Washed and cleaning equipment should be chosen and used in order not to be a source of
Contamination.

a) Equipment should be installed in such a way as to prevent any risk of error or of contamination.
b) Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.
c) Balances and measuring equipment of an appropriate range and precision should be available for production and control operations
d) Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.
e) Fixed pipe work should be clearly labelled to indicate the contents and, where applicable, the direction of flow.


f) Distilled, deionized and, where appropriate, other water pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

g) Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective.


MANUFACTURING FORMULA AND PROCESSING INSTRUCTIONS

Formally authorised Manufacturing Formula and processing Instructions should exist for each product and batch size to be maintained. They are often combined in one document.
The Manufacturing Formula should include:
i. The name of the product, with a product reference code relating to this specification;
ii. A description of the pharmaceutical form, strength of the product and batch size;
iii. A list of all starting materials to be used, with the amount of each, described using the designated name and a reference, which is unique to that material, mention should be made of any substance that may disappear in the course of processing.
iv. A statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.

The processing instructions should include:
i. A statement of the processing location and the principal equipment to be used;
ii. The methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing);
iii. Detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);
iv. The instructions for any in-process controls with their limits;
v. Where necessary, the requirements for bulk storage of the products
Including the container, labelling and special storage conditions.
vi. Any special precautions to be observed.


PERSONNEL:
The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people. For this reason there must be
Sufficient qualified personnel to carry out all the tasks, which are the responsibility of the manufacturer. Individual responsibilities should be clearly understood by the individuals and recorded. All personnel should be aware of the principles of Good Manufacturing Practice that affect them and receive initial and continuing training, including hygiene instructions, relevant to their needs.


The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality.
The manufacturer must have an organization chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.

KEY PERSONNEL
Key personnel include the head of production, the head of Quality Control, and if at least one of these persons is not responsible for the release of products the authorized person(s) designated for the purpose. Normally key posts should be occupied by full-time personnel. The heads of production and Quality Control must be independent from each other.

The head of the Production Department generally has the following responsibilities:
1. To ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;
2. To approve the instructions relating to production operations and to ensure their strict implementation
3. To ensure that the production records are evaluated and signed by an authorized person before they are sent to the Quality Control Department;
4. To check the maintenance of his department, premises and equipment;
5. To ensure that the appropriate validations are done;
6. To ensure that the required initial and continuing training of his department personnel is carried out and adapted according to need.

The head of the Quality Control Department generally has the following responsibilities:
i. To approve or reject, as he sees fit, starting materials, packaging materials, and intermediate, bulk and finished products;
ii. To evaluate batch records;
iii. To ensure that all necessary testing is carried out;
iv. To approve specifications, sampling instructions, test methods and other Quality Control procedures;
v. To approve and monitor any contract analysts;

The heads of production and Quality Control generally have some shared, or jointly exercised, responsibilities relating to quality. These may include, subject to any national regulation:
1. The authorization of written procedures and other documents, including amendments;

2. The monitoring and control of the manufacturing environment;
3. Plant hygiene
4. Process validation;
5. Training


6. The approval and monitoring of supplies of materials;
7. The approval and monitoring of contract manufacturers;
8. The designation and monitoring of storage conditions for materials and products
9. The retention of records;
10. The monitoring of compliance with the requirements of GMP;
11. The inspection, investigation, and taking of samples, in order to monitor factors, which may affect product quality.

TRAINING:
i. The manufacturer should provide training for all the personnel whose duties take them into production areas or into control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.
ii. Beside the basic training on the theory and practice of Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed. Training programmes should be available, approved by either
The head of production or the head of Quality Control, as appropriate. Training records
Should be kept.
iii. Personnel working in areas where contamination is a hazard e.g. clean areas or areas where highly active, toxic, infectious or sensitizing materials are handled should be given specific training.
iv. Visitors or untrained personnel should, preferably, not be taken into production and Quality Control areas. If this is unavoidable, they should be given information in advance, particularly about personnel hygiene and the prescribed protective clothing. They should be closely supervised.
v. The concept of Quality Assurance and all the measures capable of improving its understanding and implementation should be fully discussed during the training sessions.

PERSONAL HYGIENE

a) Detailed hygiene programmes should be established and adapted to the different needs within the factory. They should include procedures relating to the health, hygiene practices and clothing of personnel. These procedures should be understood and followed in a very strict way by every person whose duties take him into the production and control areas. Hygiene programmes should be promoted by management and widely discussed during training sessions.
b) All personnel should receive medical examination upon recruitment. It must be the manufacturer’s responsibility that there are instructions ensuring that health







Conditions that can be relevance to the quality of products come to the manufacturer’s knowledge. After the first medical examination, examinations should be carried out when necessary for the work and personal health.
c) Steps should be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products.
d) Every person entering the manufacturing areas should wear protective garments appropriate to the operations to be carried out.
e) Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas should be prohibited. In general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected, should be forbidden.
f) Direct contact should be avoided between the operator’s hands and the exposed products as well as with any part of the equipment that comes into contact with the products.
g) Personnel should be instructed to use the hand-washing facilities.
h) Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the supplementary guidelines.

BATCH PROCESSING RECORDS:
A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and processing instructions. The method of preparation of such records should be designed to avoid transcription errors. The records should carry the number of the batch being manufactured.
Before any processing, the following information should be recorded at the time each action is taken and, after completion; the record should be dated and signed in agreement by the person responsible for the processing operations:
a) The name of the product;
b) Dates and times of commencement, of significant intermediate stages and of completion of production;
c) Name of the person responsible for each stage of production;
d) Initials of the operator of different significant steps of production and, where appropriate, of the person who checked each of these operations (e.g. weighing);
e) The batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);
f) Any relevant processing operation or event and major equipment used;
g) A record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained;
h) The amount of product yield obtained at different and pertinent stages of manufacture;



i) Notes on special problems including details, with signed authorization for any deviation from the manufacturing formula and processing instructions.

PACKAGING INSTRUCTIONS:

There should be formally authorized packaging instructions for each product for pack size and type. These should normally include, or have a reference to, the following:
a. Name of the product;
b. Description of its pharmaceutical form, and strength where applicable;
c. The pack size expressed in terms of the number, weight or volume of the product in the final container;
d. A complete list of all the packaging materials required for a standard datch size, including quantities, size and types, with the code or reference number relating to the specifications of each packaging material;
e. Where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product;
f. Special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;
g. A description of the packaging operation, including any significant subsidiary operations, and equipment to be used;
h. Details of in-process controls with instructions for sampling and acceptance limits.

BATCH PACKAGING RECORDS:

A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the packaging instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained.
Before any packaging operation begins, there should be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for planned packaging operations, and that equipment is clean and suitable for use.
The following information should be entered at the time each action is taken and, after completion; the record should be dated and signed in agreement by the person(s) responsible for the packaging operations:
a) The name of the product;
b) The date(s) and times of the packaging operations;
c) The name of the responsible person carrying out the packaging operation;
d) The initials of the operators of the different significant steps;
e) Records of checks for identity and conformity with the packaging instructions including the results of in-process controls;


f) Details of the packaging operations carried out, including references to equipment and the packaging lines used;
g) Whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting;
h) The quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.


QUALITY CONTROL:
Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organization, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory.
The basic requirements of Quality Control are that:
i. Adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;
ii. Samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods are validated;
iii. Test methods are validated;
iv. Records are made, manually and/or recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were, actually carried out. Any deviations are fully recorded and investigated.
v. The finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorization, are of the purity required, and are enclosed within their proper container and correctly labeled;
vi. Records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products are formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;
vii. No batch of product is released for sale or supply prior to certification by an authorized person that it is in accordance with the requirements of the marketing authorization;
viii. Sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.

Quality Control Areas:
a) Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other.
b) Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples and records.
c) Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc.
d) Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.


Ancillary Areas:
a) Rest and refreshment rooms should be separate from other areas.
b) Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas.
c) Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.
d) Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.

QUALITY ASSURANCE:
Quality Assurance is a wide-ranging concept, which covers all matters that individually or collectively influence the quality of a product. It is the sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors.
The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that:
i. Medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice and Good Laboratory Practice;
ii. Production and control operations are clearly specified and Good Manufacturing Practice adapted;
iii. Managerial responsibilities are clearly specified;
iv. Arrangements are made for the manufacture, supply and use of the correct stating and packaging materials;
v. All necessary controls on intermediate products, and any other in process controls and validations are carried out:
vi. The finished product is correctly processed and checked, according to the defined procedures;
vii. Medicinal products are not sold or supplied before an authorized person has certified that each production batch has been produced & controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control& release of medicinal products;
viii. Satisfactory arrangements exist to ensure as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained through out shelf life;


ix. There is a procedure for self inspection and/or quality audit which regularly appraises
The effectiveness & applicability of the quality assurance system.


DOCUMENTATION:

Good documentation constitutes an essential part of the quality assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, manufacturing formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.
1. Specifications describe in detail the requirements with which the product or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation.
Manufacturing Formulae, processing and packaging instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing, and equipment operations.
Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent for the quality of the final product.
2. Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorization dossiers.
3. Documents should be approved, signed and dated by appropriate and authorized persons.
4. Documents should have unambiguous content; title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and eligible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.
5. Documents should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.
6. Documents should not be hand –written; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.
7. Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.
8. The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least one year after the expiry date of the finished product.
9. Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorized persons should be able to enter or modify data in the computer and there should be a record of changes,
And deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Back-up transfer on magnetic tape, microfilm, paper or other means should protect batch records electronically stored. It is particularly important that the data are readily available throughout the period of retention,

DOCUMENTS REQUIRED:

Specifications:
There should be appropriately authorized and dated specifications for starting and packaging materials and finished products; where appropriate, they should be also available for intermediate or bulk products.

Specifications for starting and packaging materials
Specifications for starting and primary or printed packaging materials should include, if applicable:
A description of the materials, including:
a. The designated name and the internal code reference;
b. The reference, if any, to a pharmacopeial monograph;
c. The approved suppliers and, if possible, the original producer of the products;
d. A specimen of printed materials;

1. Directions for sampling and testing or reference to procedures;
2. Qualitative and quantitative requirements with acceptance limits;
3. Storage conditions and precautions;
4. The maximum period of storage before re-examination.

Specifications for intermediate and bulk products
Specifications for intermediate and bulk products should be available if these are purchased or dispatched, or if data obtained from intermediate products are used for evaluation of the finished product. The specifications should be similar to specifications for starting or for finished products, as appropriate.

Specifications for finished products
Specifications for finished products should include:
a. The designated name of the product and the code reference where applicable;
b. The formula or a reference to;
c. A description of the pharmaceutical form and package details;
d. Directions for sampling and testing or a reference to procedures;
e. The qualitative and quantitative requirements, with the acceptance limits;
f. The storage conditions and any special handling precautions, where applicable;
g. The shelf life.







SUMMARY:
WHO defines Good Manufacturing Practices (GMP) as “that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.”
The basic requirements of GMP are:

PREMISES:
a. Premises should be situated in a suitable environment, which presents minimal risk of causing contamination.
b. Premises should be carefully maintained.
c. Lighting, temperature, humidity, & ventilation should be appropriate.

STORAGE AREAS:
a. Storage areas should be of sufficient capacity to allow orderly storage of the various categories of material and products.
b. Storage areas should be designed or adapted to ensure good storage conditions.
c. Receiving and dispatch bays should protect materials and products from the weather.

PRODUCTION AREA:
a. In order to minimize the risk of serious medical hazard due to contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products.
b. The adequacy of the working and in-process storage place should permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different medicinal products or their components.
c. Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.

EQUIPMENT:
a. Manufacturing equipment should be designed, located and maintained to suit its intended purpose.
b. Repair and maintenance operations should not present any hazard to the quality of the product.
c. Manufacturing equipment should be designed so that it can be easily and thoroughly washed and cleaning equipment should be chosen and used not to be a source of contamination.

MANUFACTURING FORMULA AND PROCESSING INSTRUCTIONS:
The manufacturing formula should include:
a. The name of the product, with a product reference code relating to this specification.
b. Descriptions of the pharmaceutical form, strength of the product and batch size.
c. A statement of the expected final yield with the acceptable limits, and of relevant intermediate yields where acceptable.





PERSONNEL:

a. The establishment and maintenance of a satisfactory system of quality assurance and the correct manufacture of medicinal products relies upon people, for this reason there must be sufficient qualified personnel to carry out all the tasks, which are the responsibility of the manufacturer.
b. Key personnel include the head of production; the head of quality control, normally full-time personnel should occupy the key posts, the head of the production and quality control must be independent from each other.
c. The manufacturer should provide training for all the personnel, whose duties take them into production area or into quality control laboratories, including the technical, maintenance and cleaning personnel.
d. Detailed hygiene programmes should be established and adapted to the different needs within the factory, which should include procedures relating to the health, hygiene practices and clothing of personnel. Hygiene programmes should be promoted by management and widely discussed during training sessions.

BATCH PROCESSING RECORDS:
a. A batch processing record should be kept for each batch processed.
b. It should be based on the relevant parts of the currently approved manufacturing formula and processing instructions.
c. The method of preparation of such records should be designed to avoid transcription errors.

PACKAGING INSTRUCTIONS:
There should be formally authorized packaging instructions for each product for pack size and type, these should include.
a. Name of the product
b. Description of its pharmaceutical form, and strength where applicable.
c. A description of the packaging operation, including any significant subsidiary operations, and equipment to be used.

QUALITY CONTROL:
The basic requirements of quality control are:
a. Adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials and intermediate, bulk and finished products.
b. Samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods validated.

QUALITY ASSURANCE:
The system of quality assurance appropriate for the manufacture of medicinal products should ensure that:
a. Production and control operations are clearly specified and Good Manufacturing Practice adapted.
b. Managerial responsibilities are clearly specified.
c. The finished product is correctly processed and checked according to the defined procedures.



DOCUMENTATION:
Good documentation constitutes an essential part of the quality assurance system:
a. Documents should be designed, prepared reviewed and distributed with care.
b. Documents should be approved, signed and dated by appropriate and authorized persons.
c. Any alteration made to the entry on a document should be signed and dated, where appropriate, the reason for the alteration should be recorded.

October 22, 2006 | 8:24 AM Comments  0 comments
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oncological clinical trials
Related to country: India

ONCOLOGICAL CLINICAL TRIALS-A Review


Sruman Bandaru
#2-10-711, Teachers Colony
Phase –I, Subedari,
Hanamkonda
Dist: Warangal
State: Andhra Pradesh,
India, PIN - 506370
E-mail: sruman_bandaru@yahoo.com


Introduction:
Clinical trials are experiments to determine the value of treatments. There are two key components to the experimental approach. First, results rather than plausible reasoning are required to support conclusions. Second, experiments should be prospectively planned and conducted under controlled conditions in order to provide definitive answers to well-defined questions.
Development of new drug involves two phases, namely drug discovery and drug development.
The stage of drug discovery involves the identification of the target, drug designing and synthesis followed by its preliminary invitro screening.

The next step is preclinical evaluation, which involves rigorous testing of efficacy and safety of the new molecule by various in vivo assays using animals. The necessary data for evaluation in humans is generated here and the test drug is now ready for its last and most crucial stage of evaluation i.e., clinical evaluation.
The clinicians in co-ordination with the pharmacists evaluate the efficacy and the safety of the sample over four stages starting from healthy volunteers and moving on to small group of patients and then larger number of patients and special groups. Phase one or clinical pharmacology forms the basis for clinical trial for any new drug and provides the link between pre-clinical and clinical research (kuhlmann, 1997). Finally, the application for FDA review and approval may be applied and the approval sought.

Clinical Research
Clinical research (CR) may be defined as an organized research conducted on human beings and is intended to provide adequate information on drug use as a therapeutic agent including its safety, usefulness and adverse effects.
The treatment can be a drug, a biological agent, a medical device experienced on human beings to test its efficiency and toxicity before it is introduced in the market.

Clinical trials require careful planning. The first result of the planning process is a written protocol. The protocol should define treatment and evaluation policies for a well-defined set of patients. It also should define the specific questions to be answered by the study and should directly justify that the number of patients and the nature of the controls are adequate to answer these questions. Typical subject headings for the protocol are shown as follows.

a) Introduction and scientific background
b) Objectives
c) Selection of patients
d) Design of study (including schematic diagram)
e) Treatment plan
f) Drug information
g) Toxicities to be monitored and dosage modifications
h) Required clinical and laboratory data and study calendar
i) Criteria for evaluating the effect of treatment and end point defination
j) Statistical considerations
k) Informed consent and regulatory considerations
l) Data forms
m) References
n) Study chairperson, collaborating participants, addresses, and telephone numbers.


Scope of Clinical Research:
Every new drug evidence from Clinical research to support its launch. Thus, whether it is a new chemical entity or an existing drug that is being marketed for new indication, Clinical studies have to be conducted. Similarly, launch of new formulations, drug delivery systems or even new fixed dose combination, requires Clinical data before it can be marketed. Hence it is obvious that the area of Clinical research holds immense scope and promise for without the supporting data drug launches are not feasible. The conduct of Clinical research is based on the GCP and ICH guidelines.

Clinical Research of Anti-cancer agents:
The first randomized clinical trial at the National Cancer Institute (NCI), commenced in 1955 for the treatment of patients with acute leukaemia. The programme in clinical trials at NCI had strong influence from the clinician and administrator, C.Gordon Zubrod, who introduced the randomized Clinical trial at NCI and organized the co-operative Clinical trial programme of cancer chemotherapy National service center (CCNSC) beginning about 1955.
From the beginning, there was acceptance of the principles of the randomization of patients and the statistical analysis of data.
The sequence of clinical trials for a new agent included the non-randomized phase I (dosage finding) and phase II (preliminary efficacy) trials as well as the phase III (comparison of treatments) trials.

Present Steps In Clinical Trials And Their Activities
Phase I trials usually test a new type of cancer treatment and are only given to a small number of participants. The purpose of a Phase I trial is to learn how to administer a treatment safely. Researchers will closely monitor the participants’ side effects and adjust dosages if need be.

Phase II trials attempt to determine patients’ responses to treatments. Typically 30 to 40 people participate in Phase II trials. In Phase II cancer treatment trials, participants are closely monitored to see if their cancerous tumors shrink during treatment. If a patient’s tumor shrink, it is responsive to treatment. If at least one-fifth of the participants "respond" to treatment, the treatment is considered successful. Researchers of Phase II trials also monitor side effects. If enough patients respond to therapy, the trial moves to Phase III.

Phase III trials enroll a large number of participants (sometimes thousands). Patients are usually divided into groups: one group receives standard therapy (control group) and the other group receives the new therapy. For example, the STAR clinical trial (Study of Tamoxifen and Raloxifene) is a Phase III trial that is enrolling 22,000 post-menopausal women 35 years of age or older who are at increased risk for developing breast cancer. The STAR Trial will compare the long-term safety of using the drugs tamoxifen and raloxifene to prevent breast cancer. As with Phase I and Phase II trials, Phase III participants are closely monitored for potentially dangerous side effects. If side effects become too severe, the trial may be canceled.








Category # of Participants Purpose
Phase I Less than 10 tests how to administer a new therapy, exam, or preventive option
Phase II 30-40 tests patient responses to a new therapy, exam, or preventive option
Phase III 100-1000+ compares new therapy exam or preventive option to a standard one
Phase IV varies For marketing purposes, to compare the effectiveness of two therapies already on the market or to study new uses of therapies
Adjuvant varies For cancer patients, determines if additional therapy will reduce chances of recurrent cancer.

Phase IV trials may be conducted for marketing purposes after a treatment has already been approved by the FDA. These trials vary in the number of participants and typically compare two treatments that are approved for similar uses to determine which one is more effective. For example, after the breast cancer drug tamoxifen was FDA approved to treat advanced breast cancer, researchers investigated whether it could also prevent breast cancer in women at high risk for the disease (tamoxifen was later FDA approved for this use too). Phase IV trials may also be conducted to study new uses or the cost effectiveness of FDA-approved treatments.
Another type of clinical trial, an adjuvant trial, attempts to determine whether additional therapy will help eliminate the possibility of a recurrence of cancer in patients at high risk of recurrence after surgery. For example, chemotherapy is found to help prevent breast cancer recurrence in many women in conjunction with breast surgery. If an adjuvant therapy is found beneficial in the trial, it may become standard treatment.

DIFFERENT PHASES OF ONCOLOGICAL CLINICAL TRIALS

Phase I Clinical Trials
The objective of a phase I trial is to determine a dose that is appropriate for use in phase II trials. Patients with advanced disease that is resistant to standard therapy are included in such trials, but it is important that the patients have normal organ function.
There are several different types of phase I trials. The most common is the phase I trial of a new cytotoxic drug. Starting with a low dose not expected to produce serious toxicity in any patients usually performs such studies. A starting dose of one-tenth the lethal dose (expressed as milligrams per square meter of body surface area) in the most sensitive species usually is used. The dose is increased for subsequent patients according to a series of preplanned steps. Dose escalation for subsequent patients occurs only after sufficient time has passed to observe acute toxic effects for patients treated at lower doses. Cohorts of three to six patients are treated at each dose level. Usually, if no dose-limiting toxicity (DLT) is seen at a given dose level, the dose is escalated for the next cohort. If the incidence of DLT is 33%, then three more patients are treated at the same level. If no further cases of DLT are seen in the additional patients, then the dose level is escalated for the next cohort. Other wise, dose escalation stops. If the incidence of DLT is greater than 33% at a given level, then dose escalation stops. The phase II recommended dose often is taken as the highest dose for which the incidence of DLT is less than 33%. Usually, six or more patients are treated at the recommended dose.
The dose levels themselves commonly are based on a modified Fibonacci series. The second level is twice the starting dose; the third level is 67% greater than the second; the fourth level is 50% greater than the third; the fifth is 40% greater than the fourth; and each subsequent step is 33% greater than that preceding it. Escalating doses for subsequent courses in the same patient is generally not done, except at low doses before any DLT has been encountered.
Traditional phase I trials have three limitations: (1) They sometimes expose too many patients to sub therapeutic doses of the new drug; (2) the trials may take a long time to complete; and (3) they provide very limited information about interpatient variability and cumulative toxicity. New trial designs have been developed to address these problems. One class of designs, accelerated titration designs.
In developing the accelerated titration designs, Simon et al, fit a stochastic model to data from 20 phase I trials of nine different drugs. New data then were simulated using the model with the parameters estimated from the actual trials, and the performance of alternative phase I designs on this simulated data was evaluated. Four designs were evaluated. Design 1 was a conventional design using cohorts of three to six patients with 40% dose-step increments and no intrapatient dose escalation. Design 2 through 4 included only one patient per cohort until one patient experienced dose-limiting toxicity or two patients experienced grade 2 toxicity (during their first course of treatment for designs 2 and 3 or during any course of treatment for design 4). Design 3 and 4 use 100% dose steps during this initial accelerated phase. After the initial accelerated phase, designs 2 through 4 resort to standard cohorts of three to six patients with 40% dose-step increments.
So called phase IB trials attempt to determine the relationship between dose of a biologic agent and both toxicity and immunologic effect. Such trials often suffer from two flaws. One is that it is assumed that cohorts of three to six patients are sufficient for relating dose to immunologic effects, without consideration of interpatient variability and measurement error of the immunologic assays. The second problem is that there is often little information about what immunologic end points actually are relevant for antitumor effects. Such studies have little potential for producing meaningful information about the dose of a biologic that should be used for subsequent trials.
Some phase I trials attempt to answer comparative questions. For example, should paclitaxel be administered before or after doxorubicin in a two-drug combination? Because of the small sample sizes of phase I trials, the maximum tolerated doses (MTDs) generally are determined imprecisely.

Phase II Clinical Trails

Patient selection
When a drug enters phase II trials, it should be tested in the patient group that is most likely to show a favorable effect but for whom no effective therapy is available. This is best accomplished by patients with maximum performance status and a minimum amount of prior chemotherapy.

Trials of single agents
There is much confusion about the appropriate objectives of phase II trials. It often is useful to distinguish between phase II trials of single agents and phase II trials of combinations. Both are called phase II trials because eligibility is limited to patients with a specific diagnosis and there is no internal control group. For most single-agent phase II trials, however, the objective is simply to determine whether the drug has activity against the tumor type in question. For this objective, response rate is an appropriate end point for evaluating the question posed by the trial. It is important to recognize, however, that tumor response is not a direct measure of patient benefit and, hence, it cannot be assumed that response rate is an appropriate end point for drawing conclusions about treatment efficacy.
Phase II trials do not have an internal control group and, hence, drawing conclusions about survival from trials is very problematic.
A variety of statistical accrual plans and sample size methods that have been developed for phase II trials have been reviewed by Simon. One of the most popular approaches is the optimal two-stage design. A number (n1) of evaluable patients is entered into study in the first stage of the trial. If fewer than a specified r1 responses are obtained among these n1 patients, then accrual terminates and the drug is rejected as being of little interest. Otherwise, accrual continues to a total of n evaluable patients. At the end of the second stage, the drug is rejected if the observed response rate is less than or equal to r/n, where r and n are determined by the design employed.

Trials of combination regimens

Many so-called phase II trials of combination regimens are conducted. The objectives of such trials are often unclear. One reasonable objective is sometimes merely to ensure that the combination is feasible and tolerable when used in a multiinstitution setting before embarking on a phase III trial. Achieving this objective does not require many patients. An alternative objective is to determine whether the new regimen is promising enough to warrant a phase III trial. Achieving this objective requires considerable planning. Consequently, many phase II trials of this type are not adequately planned and analyzed to serve any real scientific objective.
Investigators often do not distinguish between phase II trials of combinations of active agents and phase II trials of new single agents.
Thall et al. have developed Bayesian methods for planning and conducting trials in which the precision in the response probability p0 is quantified by a “prior probability distribution. These Bayesian designs provide for continual analysis of results after evaluation of response for each patient. This is difficult logistically for multiinstitution trial but provides a valid statistical basis for the intensive monitoring of cancer center or pharmaceutical industry trials in which patients may be limited or time may be critical. One begins with a prior probability distribution of response for p1 that is flat over the range 0 to 1. After each patient is evaluated on the experimental regimen, the “posterior probability distribution” for p1 is updated. This permits calculation of the posterior probability distribution for p1-p0 .

Phase III clinical Trials
Good clinical therapeutic research requires asking important questions and getting reliable answers. Some phase III trials, however, do not ask important questions. The most important clinical trials are often the most difficult to conduct. They may involve withholding a treatment established by tradition, potentially transferring patient management responsibility across specialties, standardizing procedures among physicians who believe that their way is best, and sharing recognition with large group of collaborations.
Phase III trials attempt to provide guidance to practicing physicians to help them make treatment decisions with their patients. Consequently, the trials should provide reliable information concerning end points of relevance to the patients. The major end points for evaluating the effectiveness of a treatment should be direct measures of patient welfare. Survival and symptom control are two such end points. The latter is not routinely used because it may be influenced by concomitant treatments. As stated, tumor shrinkage usually is not an appropriate end point for phase III trials because it may have little or no relation to patient benefit.
The eligibility criteria established for the trial also has a bearing on the generalizability of the conclusions; trials conducted with narrow eligibility criteria tend to be less generalizable. Narrow eligibility criteria also complicate trials logistically. Narrow eligibility criteria tend to require extensive and expensive patient workups and thereby do not facilitate broad participation, especially in an era of closely monitored medical costs. For these and other reasons, there is a trend toward broadened eligibility criteria for phase III clinical trials.

Randomization
Randomization does not ensure that the study will include a representative sample of all patients with the disease, but it does help to ensure an unbiased evaluation of the relative merits of the two treatments for the types of patients entered.
Randomization of a patient should be performed after the patient has been found eligible and has consented to participate in the trial and to accept either of the randomized options. A truly random and nondecipherable randomization procedure should be used and implemented by calling a central randomization office staffed by individuals who are independent of participating physicians.

Stratification
When important prognostic factors are known for patients in a randomized trial, it is often advisable to stratify the randomization to ensure equal distribution of these factors. This is usually accomplished by preparing a separate randomization list (or set of cards in sealed envelopes) for each stratum of patients. The stratification factors must be known for each patient at the time of randomization.
Many clinical trials use adaptive stratification methods. These methods permit effective balancing by many prognostic factors, although they typically require a computer program for their use.

Sample size
The protocol for a phase III trial should specify the number of patients to be accrued and the duration of follow-up after the close of accrual when the final analysis will be performed. Methods of sample size planning are based on the assumption that at the conclusion of the follow-up period, a statistical significance test will be performed comparing the experimental treatment to the control treatment with regard to a single primary end point.

Therapeutic equivalence trials
The objective of a therapeutic equivalence trial is generally to demonstrate that a new treatment is equivalent to standard therapy with regard to a specified clinical end point. This is contrasted to bioequivalence trials in which the objective is to demonstrate equivalence of serum concentrations of the active moiety. In some cases, investigators would like to demonstrate that the new treatment is effective as compared to no treatment but, because use of a no-treatment arm is not feasible, they attempt to demonstrate therapeutic equivalence to a standard treatment.
Therapeutic equivalence trials are problematic because it is impossible to demonstrate equivalence. If the outcomes for the two treatments are similar, one can only conclude that results are consistent with differences within specified limits.

EPIDEMIOLOGY OF CLINICAL TRIALS
Several authors have pointed out that many of the positive results reported from small trials are expected to be false-positive results. In 100 trials, suppose that there are 10 in which the experimental treatment is sufficiently better than the control such that there is an 80% chance of the difference being detected in a small or moderate-sized clinical trial. Of these 10 trials, obtaining a statistically significant difference in 8 cases (0.80 X 10) is expected. Of the remaining 90 trials, it is assumed that the treatments are approximately equivalent to the control. We would expect to obtain a statistically significant difference in 5% (4.5) of these cases. Hence, of the 12.5 (8 + 4.5) trials that yield statistically significant results, the finding is false-positive in 4.5 or 36% of the cases (4.5 / 12.5). The 36% false-positive result is striking. It depends on the assumption that only 10% of the trials represent important advances, but this assumption does not seem overly pessimistic.
An additional factor to consider is that of publication bias, which denotes the preference of journals to publish positive rather than negative results. A negative result may not be published at all, particularly from a small trial. If it is published, it is likely to appear in a less widely read journal than it would if the result were positive.
These observations emphasize that results in the medical literature often cannot be accepted at face value. It is essential to recognize that “positive” results need confirmation, particularly positive results of small studies, before they can be believed and applied to the general population.


PHARMACEUTICAL CLINICAL TRIALS
In the past, phase II studies and I were often open label and non-randomized and done in small numbers of patients. As a result, neither efficacy nor safety data were considered reliable. Randomized, double blind, placebo controlled phase III trials were therefore considered justified and ethical. During the past decade, however, the importance of properly designed early trials (phases I and II) has led to dramatic changes in their design. These changes have included both proper randomized, double blinded designs and increased sample sizes. Although there is little doubt concerning the high level of data available by the end of phase II. Because of the extensive data available, many phase III and virtually all phase IV placebo controlled trials are redundant and potentially unethical.
The mistakes are usually reported as drug failure rather than poor pharmaceutical expertise, excessive marketing influence, regulatory micromanagement, or improper patient enrolment and follow up. Approaches in the design of phase III clinical trials have also led to incorrect recommendations regarding drug dose or duration in trials considered to have been successful. Examples of mistakes include requirements for inappropriate end points for evaluating the drug, study of a single drug dose or treatment, incomplete data for calculating sample sizes, over enthusiastic reports of occurrence rates of disease by potential study centers, inadequate attention to patient inclusion or exclusion criteria, and incomplete follow up.
The ethical issues raised contribute to the global concern that activities carried out during the later stages (phases III and IV) of the present process of clinical trials are balancing on the edge of inappropriate activities, both by academic medical centers and during physician-patient interactions. These issues have been addresses by regulatory authorities in Europe by their request for comparative phase III trials of marketed drugs. But because comparative drug trials tend to require larger numbers of patients, as the goal is often to show equivalence, global pharmaceutical companies have sought approval in the United States with placebo controlled trials, then have used these to register in Europe.
It has been stated that uncommon adverse events, such as those occurring at a frequency of less than 1 per 100 patients, cannot be identified in phases I-III. Rare adverse events emerge only during post marketing surveillance. Proper evaluation of a drug’s safety requires tens of thousands of treated patients and can only be done by careful post marketing surveillance. This type of surveillance has been particularly successful in the united kingdom where the government’s “yellow card” system of reporting all drug related adverse effects has provided the healthcare community with an accurate picture of a drug’s safety profile.

ANALYSIS OF CLINICAL TRIALS

(a)Intention-to-treat analysis
One of the important principles in the analysis of phase III trials is called the ‘intention-to-treat’ principle. This indicates that all randomized patients should be included in the primary analysis of the trial. For cancer trials, this has often been interpreted to mean all “eligible” randomized patients. Because eligibility requirements sometimes are vague and unverifiable by an external auditor, excluding “ineligible” patients can itself result in bias. However, excluding patients from analysis because of treatment deviations, early death, or patient withdrawal can severely distort the results. Often, excluded patients have poorer outcomes than do those who are not excluded. Investigators frequently rationalize that the poor outcome experienced by a patient was due to lack of compliance to treatment, but the direction of causality may be the reverse.


(b)Significance levels, hypothesis tests, and confidence intervals
Medical decisions making is complicated, and clinicians frequently misinterpret statistical significance tests in search of clear-cut answers from ambiguous data. A statistical significance level for comparing outcomes represents the probability of obtaining a difference as large as that actually observed if the treatments were actually of equal efficacy and differences occur merely by chance. If differences in either direction as large in absolute value as the one actually obtained are included, the significance level is called two-sided. If the probability is calculated only for differences in the same direction as that actually obtained, the significance level is called one-sided. Generally, the two-sided significance level is twice the one-sided level.
After significance tests had been used for many years, Neyman and Pearson formalized a mathematical theory of hypothesis testing. In this theory, a study must prespecify a null hypothesis, an alternative hypothesis, and a decision rule for accepting one hypothesis and rejecting the other based on the data obtained. The theory has appealed to clinicians because it simplifies complex medical decision making by providing yes or no answers; either the difference is statistically significant or it is not.

(c)Calculation of survival curves
Most cancer clinical trials display results by showing survival curves or disease-free survival curves. Survival curves display the probability of surviving beyond any specified time, with time shown on the horizontal axis. In disease-free survival curves, it is the until recurrence or death that is shown. Other time-to-event distributions can be similarly represented using the same methods.
The most satisfactory way of representing such data is to estimate the survival function S(t). This function represents the probability of surviving more that t time units. Time t is measured from diagnosis, start of treatment, or some other meaningful time point. For randomized studies, it is best to measure time from the date of randomization. There are basically two satisfactory methods for estimating S(t). The first is the life-table or actuarial method. It frequently is attributed to Berkson and Gage or Cutler and Ederer and is appropriate when the number of patients is large. The other method is appropriate for any number of patients, but it involves more effort than the life-table method when the number of patients is large.

(d)Reporting results of Clinical trials
Simon and Wittes developed a set of methodologic guidelines for reports of clinical trials, and these guidelines have been adopted by major cancer journals. These nine guidelines are summarized below:

1. Authors should discuss briefly the quality control methods used to ensure that the data (including response assessments) are complete and accurate.
2. All patients registered on study should be accounted for.
3. The study should not have an inevaluability rate of greater than 15% for major end points
4. In randomized trials, the report should include a comparison of survival and other major end points for all eligible patients as randomized, with no exclusion other than those not meeting eligibility criteria.
5. The sample size should be sufficient to establish or conclusively rule out the existence of effects of clinically important magnitude. For “negative” conclusions in therapeutic comparisons, the adequacy of sample size should be demonstrated by presenting confidence limits for the true treatment differences.
6. The report should indicate the initial target sample size. It should specify how many interim analyses were performed and how the decisions to stop accrual and report results were made.
7. Claims of therapeutic efficacy should not be made based on nonrandomized phase II trials, unless the disease is so rare or the prognosis so poor that properly controlled randomized trials are not possible. In the later case, nonrandomized trials should use explicit historical controls for which comparability of patients can be thoroughly evaluated. Comparison of survival between responders and nonresponders is not a valid way of establishing therapeutic efficacy.
8. The patients studied should be adequately described. Applicability of conclusions to the general population of patients should be carefully discussed. Claims of subset specific treatment differences should be carefully documented statistically as more than the random result of multiple significance testing.
9. The methods of statistical analysis should be described in detail sufficient that a knowledgeable reader could reproduce the analyses if the data were available.

Levels of Evidence

Levels of Evidence and Grades of Recommendation
(as used by ASCO-Guidelines)

Level Type of Evidence
I Evidence is obtained from meta-analysis of multiple, well-designed, controlled studies. Randomized trials with low false-positive and low false-negative errors (high power).
II Evidence is obtained from at least one well-designed experimental study. Randomized trials with high false-positive and/or negative errors (low power).
III Evidence is obtained from well-designed, quasi-experimental studies such as non-randomized, controlled single-group, pre-post, cohort, time, or matched case-control series
IV Evidence is from well-designed, nonexperimental studies such as comparative and correlational descriptive and case studies
V Evidence from case reports and clinical examples

Grade Grading of Recommendation
A There is evidence of type I or consistent findings from multiple studies of types II, III, or IV
B There is evidence of types II, III, or IV and findings are generally consistent
C There is evidence of types II, III, or IV but findings are inconsistent
D There is little or no systematic empirical evidence

Note: Statements in the ESMO guidelines without grading were considered justified standard clinical practice by the experts and the ESMO faculty (expert and panel consensus).


SUMMARY
The Oncological clinical trials consists of different phases
Phase I, trial is done with an objective to determine a dose that is appropriate for use in phase II trials, traditional phase I trials have three limitations: (1) they sometimes expose too many patients to subtherapeutic doses of the new drug; (2) the trials may take a long time to complete; and (3) they provide very limited information about interpatient variability and cumulative toxicity. New trial designs have been developed to overcome these problems. One class of designs, accelerated titration designs, which include design 1, design 2, design 3 & design 4.

Phase II, the drug is tested in the patient group that is most likely to show a favorable effect but for whom no effective therapy is available. This phase dealt with the trials of single agents and trials of combination regimens
Phase II trials do not have an internal control group and, hence, drawing conclusions about survival from such trials is very problematic and various other issues were discussed

Phase III, attempt to provide guidance to practicing physicians to help them make treatment decisions with their patients, this phase mainly focused on randomization, stratification, sample size and analysis of clinical trials focused on intention-to-treat analysis, significance levels, hypothesis tests, confidence intervals, calculation of survival curves, reporting results of clinical trials , level of evidences from clinical trial and different phases of pharmaceutical clinical trials and on epidemiology of clinical trials.

Conclusion and Discussion
The greater the number of people who participate in clinical trials, the faster emerging anticancer therapies can be brought to market. Last year alone, US Oncology accrued more than 3,500 cancer patients to clinical trials - more than any single U.S. medical enterprise. With over 200 completed trials and 179 practice sites staffed for research, US Oncology is bringing the search for new therapies directly into local communities across America.

Our 1,000 research team members conduct approximately 90 clinical trials each year. While we have complete Phase 1-4 capabilities, nearly 80% of our research is in Phase 2 and 3 development stages. Last year alone, US Oncology Research successfully completed two FDA audits for clinical studies, including our gene therapy program.

The patient's rights and safety are protected in two important ways. First, any physician awarded a research grant by a pharmaceutical company or the NIH must obtain approval to conduct the study from an Institutional Review Board. The review board, which is usually composed of physicians and lay people, is charged with examining the study's protocol to ensure that the patient's rights are protected, and that the study does not present an undue or unnecessary risk to the patient. Second, anyone participating in a clinical trial in the United States is required to sign an "informed consent" form. This form details the nature of the study, the risks involved, and what may happen to a patient in the study. The informed consent tells patients that they have a right to leave the study at any time.

Patients considering participating in clinical research should talk about it with their physicians and medical caregivers. They also should seek to understand the credentials and experience of the individuals and the facility involved in conducting the study.



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