Procedure for payment of financial compensation

THE PROCEDURE FOR REPORTING SAE TO THE LICENSING AUTHORITY (DCGI) IN INDIA VARIES FOR CASE OF DEATH AND FOR CASE OTHER THAN DEATH


(A) the investigator shall report all serious and unexpected adverse events to the 

• Licensing Authority as defined under clause(b) of rule 21, the sponsor or his REPRESENTATIVE
• The sponsor of his representative whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial
• Ethics Committee that accorded approval to the study protocol,

Within 24 hours of their occurrence as per Appendix XI

IN CASE OF SAE OF DEATH
(B ) (i) the cases of serious adverse events of deaths shall be examined as under

• An independent expert committee shall be constituted by the Licensing Authority as defined under rule 21 (b) to examine cases and recommend to the licencing authority for the purpose of arriving at the cause of death and quantum of compensation in case of clinical trial related death.

• The Sponsor or his representative whosoever had obtained permission from the Licensing Authority for conducting thd clinical trial, and the investigator shall forward their reports on SAE of death after due analysis to 

1. (a) Chairman of the Ethics committee
2. (b) Chairman of the Expert committee 
3. (c) with a copy of the report to licensing authority as defined under rule 21 (b) and 
4. (d) the head of the institution where the trial has been conducted

With in 10 calendar days from the occurrence of the SAE

• The ethics committee shall forward it's report on serious adverse event of death after due analysis along with its opinion on financial compensation, if any , to be paid by the Sponsor to his representative, whosoever had obtained permission from Licencing authority within 21 calendar days of the occurrence of SAE.

• The expert committee shall examine the report of SAE of death and give it's recommendations to the Licensing Authority for the purpose of arriving at the cause of the adverse event within 30 days of receiving the report from ethics committee while examining the event, may tak into consideration, the reports of the Investigator,  sponsor or his representative whosoever had obtained permission from the Licensing Authority for conducting the clinical trial.

• In case of clinical trial related death, the expert committee shall also recommend the quantum of compensation to be paid by the Sponsor of his representative whosoever had obtained permission from the Licensing Authority as defined under rule 21(b) for conducting the clinical trial

• The licensing authority shall consider the recommendations of the Expert committee and shall determine the cause of death and pass orders as deemed necessary.

• In case of clinical trial related death, the Licensing Authority, after considering the recommendations of the expert committee, shall decide the quantum of compensation to be paid by the Sponsor or his representative, whosoever had obtained permission from the Licensing Authority for conducting the clinical trial and shall pass orders as deemed necessary within three months of receiving the report of the serious adverse event.

IN CASE OF SAE OTHER THAN THAT OF DEATH

• The Sponsor or his representative whosoever had obtained permission from the Licensing Authority for conducting thd clinical trial, and the investigator shall forward their reports on SAE  after due analysis to 

1. (a) Chairman of the Ethics committee
2. (B) licensing authority as defined under rule 21 (b) and 
3. (d) the head of the institution where the trial has been conducted

     Within 10 calendar days of occurrence of the SAE

• The ethics committee shall forward it's report on serious adverse event after due analysis along with its opinion on financial compensation, if any , to be paid by the Sponsor to his representative, whosoever had obtained permission from Licencing authority within 21 calendar days of the occurrence of SAE.

• The licensing authority shall determine the cause of injury and pass orders as deemed necessary. The licensing authority shall have the option to constitute an independent expert committee, wherever considered necessary, to examine such serious adverse Events of injury,  which will recommend to the licencing authority for arriving at the cause of the injury and also the quantum of compensation in case of clinical trial related injury to be paid by the Sponsor or his representative whosoever had obtained permission from the Licensing 6 as defined under rule 21 (b) for conducting the clinical trial.

• In case of clinical trial related injury the licensing authority shall decide the quantum of compensation to be paid by the Sponsor or his representative whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial and shall pass the order as deemed necessary within three months of receiving the report of the SAE.

APPLICABLE FOR ANY SAE

The Sponsor or his representative whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial shall pay the compensation in case of clinical trial related injury or death as per the order of the licensing authority as defined under rule 21 (b) within 30 days of receipt of this order.

Safety Reporting Requirements in India

As per the Notification of Ministry of Health and Family Welfare dated 30th January 2013, there is a change in safety reporting requirements in clinical trials.

A draft rules for the same to amend the Drugs and Cosmetic Rules 1945 (which is a requirement as per Drugs and Cosmetic Act of 1940) was published were in the gazette on 18th Nov 2011 inviting objections and suggestions from all persons likely to be affected thereby before the expiry of a period of 45 days from the date on which the copies of the official gazette of the said notification were made available to the public. The ops were made available to the public on 24th November, 2011.

Definitions:

Gazette of India -

The Gazette of India is a public journal and an authorised legal document of the Government of India, published weekly by the Department of Publication, Ministry of Urban  Development. As a public journal, the Gazette prints official notices from the government. It is authentic in content, accurate and strictly in accordance with the Government policies and decisions. The gazette is printed by the Government of India Press.




After the suggestions and objections received from public were received and considered by Government of India, the following amendment to the Drugs and Cosmetics Rules, 1945 took place. THIS IS KNOWN AS THE FIRST AMENDMENT OF THE DRUGS AND COSMETIC RULES, 2013. They came into force on the date of their publication in the official gazette I.e., 30th January 2013.





COMPENSATION IN THE CASE Of DEATH OR INJURY

1. In case of injury occurring to the clinical trial subject, he or she shall be given free medical management as long as required.
2. In case the injury occurring to the trial subject is related to the clinical trial, such subject shall also be entitled for financial compensation as per order of the licensing authority defined under clause (b) of rule 21, and the financial compensation will be over and above any medical expenses incurred on the medical management of the subject.
3. In case of clinical trial related death of the subject, his/her nominee(s) would be entitled for financial compensation, as per the order of the Licensing Authority defined under clause (b) of rule 21, and the financial compensation will be over and above any expenses incurred on the medical management of such subject.
4. The expenses on medical management and financial compensation in case of clinical trial injury or death of the trial subject will be borne by the sponsor of the clinical trial.
5. Any injury or death of the subject occuring in clinical trial due to the following reasons shall be considered as clinical trial related injury or death and the subject or his/her nominee(s), as the case may be, are entitled for financial compensation for such injury or death:

• Adverse effect of investigational products
• Violation of the approved protocol , scientific misconduct or negligence by the sponsor or his representative or the Investigator
• Failure of investigational product to provide intended therapeutic effect
• Use of placebo in a placebo-controlled trial
• Adverse effects due to concomitant medication excluding standard care, necessitated as a part of approved protocol.
• For injury to a child in -utero because of participation of parent in clinical trial
• Any clinical trial procedures involved in the study.

6. The Sponsor, whether a pharmaceutical company or an institution shall give an undertaking along with the application for clinical trial permission to the Licensing Authority defined in clause (b) of Rule 21, to provide compensation in the case of clinical trial related death for which subjects are entitled to compensation.

7. In case the sponsor fails to provide medical management for the injury to the subject and/or financial compensation to the trial subject for clinical trial related injury or financial compensation to the subjects nominee(s) in case of clinical trial related death of the subject, the Licensing Authority may after giving an opportunity to show cause why such an order should not be passed, by an order in writing , stating the reason thereof, suspend or cancel the clinical trial and/or restrict Sponsor including his representatives to conduct any further clinical trials in the country or take any other action deemed fit under the rules.


In the said rules, in Schedule Y, in paragraph 2 relating to Clinical Trial ,
(A) in subparagraph (2) relating to Responsibilities of the Sponsor (i) clause (iv) shall be substituted by the following, namely:


SPONSOR RESPONSIBILITY

SAE OF DEATH
------------------------
(Iv) any report of serious adverse event of death occuring in clinical trial,  after due analysis shall be forwarded by the sponsor to

• Chairman of ethics committee
• Chairman of k committee constituted by Licensing Authority
• copy of the report to licensing authority
• Copy of report to head of the institution where trial has been conducted

These reports have to be sent within 10 calender days of occurrence of the SAE of DEATH

SAE OTHER THAN DEATH
-------------------------------------------
The report of SA other than death after due analysis shall be forwarded by the sponsor to :

• Licensing Authority
• Chairman of Ethics committee
• Head of institution where trial has been conducted.

Within 10 calendar days of occurrence of the  SA

(B ) after clause iv,  the following shall be inserted, namely:

(V) in case of injury or death occuring to the clinical trial subject, the sponsor (whether a pharmaceutical company or an institution) or his representative, whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial, shall make payment for medical management of the subject and also provide financial compensation for the clinical trial related injury or death in the manner as prescribed in Appendix XII

(vi) the sponsor (whether a pharmaceutical company or an institution) or his representative, whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial, shall submit details of compensation provided or paid for clinical trial related injury or death, to the Licensing Authority within thirty days of the receipt of the order from licencing authority.

(C) RESPONSIBILITIES OF THE INVESTIGATOR

Investigator shall report all serious and unexpected adverse events to the

• Licensing Authority as defined under clause (b) of Rule 21, 
• the Sponsor or his representative, whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial and
• the ethics committee that accorded approval to the study protocol within 24 hours of their occurrence as per Appendix XI, and the said Licensing Authority  shall determine the cause of injury or death as per the procedure prescribed under Appendix XII and pass orders as deemed necessary.

In sub paragraph (3) relating to Responsibilities of the Investigator(s)-

(i) the sub paragraph (3) shall be numbered as (3) (i);
( ii) in the so numbered clause (i) the words and figures "sponsor within 24 hours and to Ethics committee that accorded approval to the study protocol within 7 working days of their occurrence shall be substituted by "

• licensing authority defined under clause (b) of rule 21, 
• the sponsor or his representative, whosoever had obtained permission from the Licensing authority for conduct of the clinical trial,and 
• Ethics Committee which accorded approval to the study protocol , within 24 hours of their occurrence.

The report of the SAE of death, after due analysis,  shall be forwarded by the Investigator to the

•  chairman of the Ethics committee
• Chairman of the expert committee constituted by the licensing authority.
• Head of institution where the trial has been conducted

Within 10 calendar days of occurrence of the SAE.

(iii) after so numbered clause (i) the following shall be inserted, namely:
(ii) the investigator shall provide information to the clinical trial subject through informed consent process as provided in Appendix V about the essential elements of the clinical trial and subject's right to claim compensation in case of trial related injury or death. He shall also inform the subject or his/ her representative whosoever had obtained permission from the Licensing Authority for conduct of the clinical trial for the purpose of making claims in the case of trial related injury or death.

(d) in clause (5) relating to RESPONSIBILITIES OF ETHICS COMMITTEES after sub clause (iii) the following sub clause shall be inserted, namely:

(iv) IN CASE OF SAE of DEATH occuring to the clinical trial subject , the ETHICS COMMITTEE shall forward it's report  on SAE of death , after due analysis, along with its opinion on the financial compensation, if any, to be paid by the Sponsor or his representative, whosoever had obtained permission from the Licensing Authority as defined under rule 21(b) for conducting the clinical trial to the

• Chairman of expert committee constituted by Licensing Authority
• Copy of report to licensing authority

Within 21 days of occurrence of the SAE of death.

IN CASE OF SAE other than that of death occuring to the clinical trial subject , the ETHICS COMMITTEE shall forward it's report  on SAE , after due analysis, along with its opinion on the financial compensation, if any, to be paid by the Sponsor or his representative, whosoever had obtained permission from the Licensing Authority as defined under rule 21(b) for conducting the clinical trial to the

•  Licensing Authority

Within 21 days of occurrence of the SAE of death.

Electricardiogram (ECG) Interpretation

To interpet the ECG, a good understanding of the electrophysiology of the heart is required.

Important thing to remember, that the ECG is generally recorded at a speed of 25mm/second. This means that
a big box,  which had a 5mm length is covered in 0.2 second. And the 5 small boxes each present in a big box are 1 mm in length and are covered in 0.04 second each.



Therefore in order to calculate heart rate, we need to know the amount of area covered by the ECG strip in 60 seconds. This will be 25*60 = 1500 mm. Thus the number of RR intervals in this 1500 mm will be heart rate or alternatively the number of RR intervals in 25mm strip can be multiplied by 60 or 300/number of big boxes between RR interval

Systematic analysis of the ECG:
1. Analyse the rate - of the atria and the ventricles
2. Analyse the rhythm - is it regular, is it regularly irregularly or irregularly irregular.
3. Analyse the PR interval (0.2 sec, less than one big box). Is it constant?
4. Analyse the RR interval
5. Analyse the p wave- is there a p wave?, is there a p wave before every QRS complex ?, is there a QRS complex before every p wave?
6. QRS interval length is not more than 0. 12 seconds i.e., not more than 3 little boxes, is there a delta wave?

Normal Sinus Rythm - this should be interpret systematically
1. RYTHM: Look at the RR interval , is it of the same length between complexes if yes then is the Rythm is constant?
2. HEART RATE: The heart rate can be calculated by dividing 300 by the number of large boxes between RR interval. Therefore if there are 5 big boxes between RR waves then the rate is 60 and if there are 4 big boxes then the rate is 75. However if the boxes counted are 4 big boxes plus 3 small boxes then the heart rate will be between 60 and 75 i.e. 67
3. Is there a p wave for each QRS and QRS complex for each p wave.
4. The QRS complex should not be more than 3 small boxes i.e., 0.12 seconds.

BRADYCARDIA
If the heart rate is calculated to be less than 60 it means the patient is suffering from bradycardia. If p waves preceed the QRS complex then this means that the Sinus node is driving the QRS complex there it is in Sinus Rythm.
Causes for sun us bradycardia are:
increased vagal tone, SA node disturbances, drugs, also seen in athletes
No treatment is required for bradycardia unless it is also causing ventricular irritability or hypotension.

Autoimmune Thrombocytopenia

Autoimmune Thrombocytopenia

Immune thrombocytopenic purpura (ITP) is characterised by antibodies to glycoproteins IIb/IIIa complex on platelets. The mechanism by which these antibodies originate is not known. Platelets with antibodies on their surface are trapped and removed by the spleen. 
Platelets are released into bloodstream by megakaryocytes. Development of megakaryocytes is dependent on thrombopoetin (TPO) and certain cytokines( Interleukin 3, 6 and 11)

Two forms of ITP are known:

1) An Acute Form - sudden onset

- this is a self-limiting illness and occurs almost exclusively in children (5 cases per 100,000 persons)

-occurs in both male and female children with equal frequency.

-bleeding which occurs is usually mild 

- petechiae and ecchymoses are observed following mild trauma when  platelet counts fall in between 20,000/µL -50,000/µL

-generalized petechiae, ecchymoses, and mucosal bleeding occur when platelet counts fall to less than 10,000/µL.

-widespread ecchymoses, hemorrhagic b)
llae, and retinal hemorrhage occur when platelet counts fall below 2000/µL.

Diagnosis is based on findings on physical exsm and periphrral smear. On examinition petechiae,purpura and ecchymoses are noticed. On peripheral smear, a decreased number of platelets are moticed. Often, the smear shows giant platelets, which is a reflection of increased thrombopoietin-induced stimulation of the bone marrow. Bond marrow examinition shows increased megakaryocytes.

Any child with isolated thrombocytopenia ( and normal WBC or RBC count) mostly is diagnos
 With ITP.

2) A Chronic Form - insidious onset
- this form is occurs mostly in adults (3-5 cases per 100,000 persons) and rarely in children.
-more common in females
Bleeding manifestations are similar to those seen in acute form of ITP.
Diagnosis is made by excluding other causes such as thrombotic thrombocytopenic purpura, drug induced thrombocytopenia, hypertensive disorders of pregnancy, hemolytic uraemic syndrome, post transfusional thrombocytopenia etc.

TREATMENT OF ITP IN CHILDREN
-acute ITP is self limiting therefore is generally not treated.
-Treatment is generally when platelet levels fall bellow 20,000/microlitre.
-intravenous gamma globulins these result in a prompt rise in the platelet count.
-The adverse effects of IVIG include fever, nausea, vomiting, and, occasionally, renal failure. IVIG is also very expensive compared with prednisone and is not available in all countries.
- Corticosteroids

Oral prednisone (4 mg/kg, with tapering and discontinuation by day 21) or IV methylprednisolone (30 mg/kg for 3 d) is also effective, although recovery is not as quick as with IVIG. The mode of action of prednisone is probably multifold, decreasing antibody production, increasing platelet formation, decreasing macrophage-mediated clearance of platelets in the spleen, and immunomodulating the immune response.

-The combination of steroids and IVIG is synergistic and can be used in patients with imminent hemorrhage.

-Inducing a mild hemolytic state by administering anti-D D  immunoglobulin (25-50 μg/kg for 2 d) is also effective in individuals who are Rh positive. This therapy is less expensive than IVIG. The limitations include a dose-dependent mild anemia, inapplicability in individuals who are Rh negative, and a limited response in patients who have undergone splenectomy.

With these modalities, the platelet counts in most children can be maintained at more than 30,000/µL until spontaneous remission occurs.

TREATMENT OF CHRONIC ITP

1. Steroids

• Generally treatment is started when platelets fall below less than 50,000/microlitre or bleeding manifestations are present.
• Steroids: a course of prednisone(1mg/kg) is generally tried initially and continued until the platelet count reaches 50,000/microlitre and then gradually tapered.

2. Splenectomy

Incase steroids fail splenectomy is considered as spleen is effective is the major site of destruction and the major source of antiplatelet antibody synthesis. Before splenectomy, patients should receive a pneumococcal vaccine.

3. Intravenous gamma globulins

• IVIG (1 g/kg/d for 1-2 d) induces a short-term increase in the platelet count, starting within several days and lasting approximately 2-3 weeks, both in patients who have undergone splenectomy and in those who have not. No clear evidence indicates that repeated infusions induce a lasting remission. Significant adverse effects include hypotension and renal failure.
• Anti-D immunoglobulin (WinRho, 50-75 μg/kg IV) is also as effective as IV immunoglobulin in Rh-positive adults with an intact spleen. Rarely, massive intravascular hemolysis with DIC and occasional death has occurred with the use of anti-D immunoglobulin.
• Both IVIG and anti-D immunoglobulin are relatively expensive therapy for adults compared with steroids, and these agents are primarily used on an interim basis during a crisis (eg, before splenectomy or major surgery).
• Approximately 10-20% of patients who undergo splenectomy remain thrombocytopenic and continue to have a bleeding risk that requires continued treatment. Both steroid therapy and splenectomy are considered to have failed in these patients, and the patients are challenging to treat. An accessory spleen should be excluded as the cause of treatment failure after splenectomy.

4. Thrombopoietin Receptor Agonist

Stimulation of megakaryopoiesis by  thrombopoietin receptor agonists improves the platelet count. Two thrombopoietin receptor agonists for the treatment of chronic refractory ITP are

 1) Eltrombopag is an oral nonpeptide thrombopoietin receptor agonist that interacts with the transmembrane domain of the thrombopoietin receptor and induces megakaryocyte proliferation and differentiation. 

Eltrombopag is given in doses of 25-75 mg orally daily. The adverse effects include hepatotoxicity, worsening of cataracts, and increased bone marrow reticulin fibers.

2) Romiplostim (AMG-531) is another thrombopoietin receptor agonist, consisting of human immunoglobulin Fc region covalently linked to a peptide sequence that binds to and activates the thrombopoietin receptor. 

Weekly subcutaneous doses of 1-7 μg/kg, romiplostim can increase the platelet count in chronic ITP. The adverse effects include bone marrow reticulin formation.

The responses to thrombopoietin receptor agonists take 10-15 days, and, hence, they are unlikely to replace steroids or intravenous immunoglobulins as initial therapy. Currently, these agents are recommended for ITP patients whose conditions are refractory to previous treatments, including splenectomy.

Hemostatsis

 Platelets,  coagulation factors and endothelial cells lining the blood vessels are essential for adequate hemostatsis. The platelets are formed from megakaryocytes and circulate in the blood for 7-10 days. Megakaryocytes are present in the bone marrow and platelets are formed from their fragmentation.

When the endothelial lining is disrupted and underlying matrix is exposed , platelets and coagulation factors interact to plug the aberration by forming a thrombosis. The plug is formed by platelets in combinition with subendothelium von Willibrand factor and membrane glycoproteins. This is known as primary hemostatsis. Defects in platelets result in ineffective primary hemostatsis. 

In response to injury, the platelets form and initial plug on the site of injury and later on the coagulation factors support this plug with fibrin mesh.

Defects in coagulation factors result in ineffective secondary hemostatsis.

Primary hemostatic disorders result in  prolonged bleeding time, and the characteristic physical examination findings such as petechiae and purpura. In comparison, defects in secondary hemostasis result in delayed deep bleeding (eg, into muscles and joints) and the characteristic physical examination finding is hemarthrosis. 
Hemarthrosis and muscle hematomas are not present in primary hemostatic disorders.

Pulse Polio Programme: success in India

Poliomyelitis often called polio or infantile paralysis, is a disease caused by a the spread from person to person of the polio virus. 

Most patients suffering from polio dont have any symptoms however in about  1% of cases, the virus enters the central nervous system leading to muscle weakness and acute flaccid paralysis which most often involves the legs. The legs of the affected person are paralysed for life.

Government of India launched the Pulse Polio programme, an immunization campaign which deals with vaccinating all children under age of 5 years against polio virus,   to eradicate polio in India. The programme started in India in 1978 and the last polio case was seen in 2011. In 2012, India was removed from the list of polio endemic nations and in 2014 , India was declared polio free. This is a big feat for a developing nation like India which has a population of over 1 billion people.

The success story of polio eradication is a story of innovation,  perseverance, dedication, commitment and partnership.  This programme has been successful due to participation of both the civil society and the government.

This project deals with the ways to fight poliomyelitis through a large scale immunisation programme, co-operating with various international institutions, state governments and Non Governmental Organisations, as part of the Global Polio Eradication Initiative, spearheaded by Rotary International, the World Health Organization, UNICEF, and the U.S. Centers for Disease Control and Prevention.

Major Success Factors are:
1. Strong, political and financial commitments
2. Meticulous planning, execution and monitoring
3. Generation of high quality data and objective evidence
4. Ongoing tactical and scientific innovations based on data analysis and research
5. Perseverance and resilience to overcome the range of challenges
6. Strong, enduring, effective partnership.

The programme required detailed microlevel planning such as house to house vaccination, tools to collect data child vaccination of every household ,putting a mark on every vaccinated childs finger in  order to identify unvaccinated children, putting a mark on every house in which children remain unvaccinated. In a population of over one billion people this was a tedious task but through combined efforts it was accomplished.

Two major challenges which have been seen and tackled during the programme are (1) failure to vaccinate (2) vaccine failure

The first challenge i.e., failure to vaccinate was tackled by massive human resource development for community mobilizations, reaching out to community leaders etc.

For example, the Kosi river belt in India is an area which constantly experiences heavy floods thereby making the area inaccessible. Thus it was a challenge to eliminate polio from this area and 10-15%  children were always missed during campaigns. This area was identified during surveillance programmes and a multipronged approached was taken to achieve high coverage in this area.

The second challenge i.e., vaccine failure was tackled by observing response to the three available vaccines i.e., monovalent, bivalent and trivalent. On realising that bivalent vaccine was most effective, this vaccine was used to achieve high elimination rates.

Many such road blocks were tackled effectively and timely to make india completely polio free. The last case of a polio patient a young girl called Ruksana was seen in 2011. Since 2011, no news cases have been detected however surveillance continues as unless polio is eradicated around the world , possibility of eliminating the virus from India completely is  distant possibility.

The success story of polio programme in India sets an example for the other countries which have not been able to root out polio completely. It is a testament that much can be achieved by concerted efforts of both thd civil society and thd government.

Acne

Introduction
Acne is a chronic inflammatory disease of the pile sebaceous unit in skin. It presents with skin lesions such as comedones (open and closed), papules, pustules and nodules which generally affect the face but may also affect the back, chest and upper arms. Acne, if not treated may become severe and leave scars and may have a psychological impact on the patient. Generally affects adolescents and young adults.


Clinical Presentation
Open comedones or black heads and closed comedone or whiteheads do not present with local inflammation therefore are considered to be non inflammatory lesions. Papules, pustules, nodules and cysts are considered to be inflammatory lesions. Local symptoms of acne can be pain , tenderness and /or erythema.

Grading of Severity
Comedones Acne: comedones but no inflammatory lesions
Mild Acne: multiple comedones with few papulopustules 
Moderate Acne: has comedones, inflammatory papules and pustules
Severe Acne: multiple papulopustules and nodules great than 5mm. Scarring is often evident.

Pathogenesis
Increased sebum production by sebaceous gland, hyperkeratinization of the follicle,colonisation of the follicle by a microorganism 'propionibacterium acnes' followed by an inflammatory reaction.

Malaria: life cycle

"Humanity has but 3 great enemies: fever, famine and war; of these by far the greatest, by far the most terrible is Fever." William Osler.

Malaria
Malaria is a protozoan disease transmitted by the bite of infected Anopheles mosquitoes. It is the most important parasitic diseases of humans, with transmission in 103 countries and causing between 1 and 3 million deaths each year. Malaria remains today a heavy burden on tropical communities, a threat to non endemic countries, and a danger to travelers.

LIFE CYCLE
Four species of the genus Plasmodium cause nearly all malaria infections in humans. These are P. vivax, P. ovale, P. malariae, P. falciparum.

1. Human infection begins when a female anopheles mosquito inoculates plasmodium sporozoites from its salivary glands during a blood meal. 
2. These microscopic motile forms of the malaria parasite are carried rapidly via the blood stream to the liver, where they invade hepatic parenchymal cells and begin a period of asexual reproduction. They areknown as hypnozoites. By this amplification process (known as intra hepatic or preerythocytic schizogony or merogony)
3. A single sporozoite then produces 10,000 to >30,000 daughter merozoites. 
4. The swollen liver cell eventually bursts, discharging motile merozoites into the bloodstream.
5. These then invade the red blood cells and multiply 6-20 fold every 48 to 72 hours.
6. When parasite densities reach near about 50 per microlitre of blood, the symptomatic stage of infection begins.
7. In P . vivax and P . ovale infections , a proportion of the hypnozoites lie dormant and do not divide. They can lie dormant from a period of 3 weeks to a year or longer before they begin asexual reproduction. These dormant hypnozoites are the cause of relapses that characterize infection with these 2 species.
8. After merozoites enter bloodstream they rapidly invade erythrocytes and become trophozoites.
9. Attachment to erythrocyte is through the a special receptor on the erythrocyte. For P . vivax , this receptor is related to Duffy blood group antigen Fya and Fyb . Therefore west Africans who carry the Duffy fyfy phenotype are resistant to P . vivax malaria.
10. During early stage of development, the ring stage of 4 parasitic species appear appear similar under microscopy. As trophozoites enlarge, species specific characteristics become apparent. By the end of 48 hour intraerythocytic life cycle (72 hours for P . malariae ), the parasite has consumed nearly all haemoglobin and grown to fill most of the RED and is now called a schizont.
11. Multiple nuclear divisions take place known as schizogony or merogony and the RBC ruptures to release 6-30 daughter merozoites. These further invade more RBC
12. After a series of asexual cycles in case of P . falciparum or immediately after release from the liver, in case of the other 3 species , some of the parasites develop into sexual forms called gametocytes that can transmit malaria.
13. After these gametocytes are ingested by a female anopheles mosquito,  the male female forms form a zygote in the insects midgut. The zygote matures into a ookinete,  which penetrators and encysts in the mosquitos gut wall . the resulting oocyte enlarges until it burns to release  a large number of motile sporozoites.

Writing a Good Clinical Study Report

At the end of a clinical trial it is important to analyse data in detail and present it well. Writing a report is a regulatory requirement and only on submitting the report complete with proceedings of the trials and results on analysis of data gathered during the trial will the next step in the development plan of a drug be granted.

Steps to writing a good Clinical Study Report include a good knowledge of widely accepted contents of the report. ICH has a whole guidance devoted to writing a clinical study report (E3). It is a detailed document on contents of the report.

Each section  will be discussed below:

Definition of a Clinical Study Report (CSR) : CSR is a-
1. Integrated full report of an individual study I.e., where in clinical and statistical descriptions, presentations and analyses are integrated into a single report.
2.Report of any drug which can be for therapeutic, diagnostic or prophylactic use
3 . Report of a study conducted in patients
4. Report in which Tables and figures are incorporated in the main text of the report or at end of text while the appendices of the report contain protocol, sample CRF, investigator related information, information related to test drug/investigational product, technical statistical document, related publication, patient data listings,  technical statistical details such as derivations , computations, analyses and computer output.

The report should provide a clear explanation of how the critical design features of the study were chosen and enough information on plan, method and conduct of the study so that there is no ambiguity on how the study was carried out.

The report and its appendices should provide enough  individual patient data,including demographic data,  baseline data and details of analytical methods used so as  to enable replication of result if authorities wish to do so.

Structure and Content of the report:
As per ICH format, there are 16 sections in total of the study report. The 16 sections are mentioned below in the order described in the guidance.

1. TITLE PAGE
2. SYNOPSIS
3. TABLE OF CONTENTS
4. LIST OF ABBREVIATIONS
5. ETHICS
6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
7. INTRODUCTION
8. STUDY OBJECTIVES
9. INVESTIGATIONAL PLAN
10. STUDY PATIENTS
11. EFFICACY EVALUATIONS
12. SAFETY EVALUATIONS
13. DISCUSSION AND OVERALL CONCLUSION
14. TABLE, FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN TEXT
15. REFERENCE LIST
16. APPENDICES

The details of each section is presented below:

1. TITLE PAGE:
The title page should contain
I. Study title
II. Name of the test drug/investigational product
III. Indication studied
IV. If not apparent from the title then a brief description of the study design
V. Name of the sponsor
VI. Protocol identification ( code or number)
VII. Study initiation date(first patient enrolled), date of early study termination, study completion date(last patient completed)
VIII. Name and affiliation of principal or coordinating investigator or sponsors responsible medical officer
IX. Name of sponsors signatory
X. Statement indicating that the study was performed in compliance with Good Clinical Practice, including archiving of essential documents.
XI. Date of report.

2. SYNOPSIS
The synopsis should summarise the study and should generally
Be limited to 3 pages. The synopsis should include numerical data to represent results and not just text and p values. Basically a clear understanding of the CSR should be possible from the synopsis.

3 . TABLE OF CONTENTS
It should have details of each section and the page numbers at which these sections are located

4. LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
A list of abbreviations and unusual terms should be provided in this section . Abbreviated terms should be spelled out and the abbreviations indicated I  the parenthesis in the first appearence in the text.

5. ETHICS
Ethical conduct of a trial is an important aspect of GCP and this section is devoted to giving evidence on the same. Under this section details of ethics committee involved in the trial, ethical principals followed during the trial and freely given informed
consent are mentioned.

6. INVESTIGATOR AND STUDY ADMINISTRATIVE STRUCTURE
Details of the team at site I.e., the principal Investigator,
coordinating investigator; details of steering committee , CRO's,  statistician, monitoring, central laboratory , author of the report should be mentioned.

7. INTRODUCTION
 The introduction should contain a brief statement generally of one page which should clearly mention the place the study in the Context of the development programme. It should mention the rationale,  aims, target population, treatment, duration, primary endpoints of the trial. Any guidance referred to during predation of the protocol or any meetings / discussion with the regulatory authority with respect to protocol development can be mentioned here.

8. STUDY OBJECTIVES
The overall purpose of the study should be mentioned here.

9. INVESTIGATIONAL PLAN
 9.1 Overall study design and plan should be described briefly and clearly by using charts or diagrams.
The information to be provided is:
- Treatment studied
- Population and number of patients studied
- level and method of blinding and masking
- kind of control used
- method of assignment to treatment
-sequence and duration of all study periods
- preferably display of the design graphically with a flow chart

9.2.  Discussion of study design, including choice of control groups
Blinding, randomization and choice of control should be discussed. Merits and demerits to be mentioned

9.3. Selection of Study Population
Inclusion, exclusion and withdrawal criteria should be mentioned

9.4 Treatments
Treatments administered (dose, route, method of administration), identity of the investigation product (batch number, formulation,  strength) , if more than one batch is used then the patients receiving each batch should be identified , source of investigational product and comparator should be provided, method of resupply in case of limited shelf lives,method of assigning to different treatment groups, selection of doses in the study, selection and timings of dose for each patient, blinding, prior and concomitant medication, treatment compliance.

9.5 Efficacy and Safety variables

9.6 Data quality assurance

9.7 statistical methods used in the protocol and determination of sample size.

9.8 changes in conduct of the study or planned analysis.

10. STUDY PATIENTS
Disposition of patients, protocol deviations

11. EFFICACY EVALUATIONS
Data sets analysed, demographic and other baseline characteristics,  measurement of treatment compliance,  efficacy results and tabulations of individual patient data.

12. SAFETY EVALUATIONS
Safety related data to be analysed at 3 levels. First , the extent of exposure; second, more common adverse events; third serious adverse events and other significant adverse events should be identified.

13. DISCUSSION AND OVERALL CONCLUSION
The efficacy and safety results and the relationship of risks and benefits should be briefly summarised and discussed.

14. TABLES FIGURES AND GRAPHS REFERRED TO BUT NOT INCLUDED IN TEXT - self explanatory

15. REFERENCE LIST
A list of articles referred to in the text should be provided.

16. APPENDICES
16.1
I.  Protocol and protocol amendments
II. Sample CRF
III. List of IRBs/IECs
IV. List of investigators including CVs
V. Signature of investigators or sponsors responsible medical expert
VI. Listing of patient receiving test drug/ investigational products

VII. Randomization schemes and codes
VIII. Audit Certificates
IX. Documentation of statistical methods
X. Documentation of inter laboratory standardisation methods and quality assurance
XI. Publications based on the study
XII. Important publications referenced in the report

16.2
PATIENT DATA LIST ING

16.3
CRF

16.4
Individual patient data listings

Deep Vein Thrombosis

Deep venous thr:
mboembolism can be divided into 2 types (VTE)
1. Deep venous thrombosis (DVT)
2. Pulmonary embolism (PE)

DVT occurs due to coagulation of blood (formation of a thrombus) in one of the deep veins. DVT generally affects the veins in legs or arms. More common is lower extremity DVT. This results in pain and swelling in the affected limb.

If DVT is not treated,  the throbs can get fragmented and can move up the arteries in the Lung. This can be potentially life threatening.

Diagnosis:
Gold standard is Venography
Alternatively Ultrasound examination may also be done.

Pathophysiology:
Virchow triad - venous stasis, activation of blood coagulation and vein damage. These 3 factors are responsible for development of DVT.

Venous stasis can be a result of any factor that slows or obstructs blood flow. This leads to increased viscosity of blood and microthrombi formation. Due to obstruction of blood , the microthrombi are not washed away and may increase in size.

Etiology
Can be due to acquired or congenital factors
Acquired factors can be those which result in prolonged immobilisation for e.g hospitalizations after surgery, bedridden patients, stroke, paraplegia or transcontinental flights.
Congenital factors such as enzyme deficiency or mutation, anatomic defects can lead to DVT.

Risk factors
1. History of previous VTE
2. Cancer
3. Age older than 75 years
4. Acute infectious disease
5. Obesity
6. Orthopedic surgery
7 . immobility for longer than 3 days
8. Pregnancy
9. Burns
10. Oral contraceptives

Treatment
Goal of therapy is to prevent PE and prevent post thrombotic syndrome.

I. Mainstay is anticoagulation. This therapy treats 90% of patients.
Agents used:
1. Heparin derivatives: unfractionated and low molecular weight heparin(LMWH). Act by inhibiting activated factor X. Bleeding complication is mainly attributed to higher molecular fragments and lower with LMWH
 2. Factor Xa Inhibitors
A. Fondaparinux - direct inhibitor of factor X . administered as a once daily subcutaneous injection.
Monitoring of aPTT and PT not required.
3. Rivaroxaban - oral factor Xa inhibitor approved for treatment of DVT and PE
4. Apixaban - approved both for treatment as well as prophylaxis of DVT and PE.
5. Dabigatran - approved for treatment of DVT and PE and prevention of PE in stroke patients


Treatment for first episode should be for atleast 3 months and for recurrent episodes for a year.

Complications of therapy: hemorrhagic complications are yhe most common adverse events of anticoagulation therapy. Bleeding can occur in 3-10% people on 3-6 month anticoagulation therapy.

Emerging agents: razaxaban,  idraparinux,  bivalirudin,  lepirudin,  ximelagatran


II. Thrombolysis

III. Surgical thrombectomy

Prophylaxis of DVT
- Pneumatic compression
- aspirin
- warfarin
- heparins: unfractionated and LMWH( enoxaparin,  deltaparin , nadroparin, tinzaparin,  ardeparin)
- Rivaroxaban

-Apixaban

Burn : Classification and Treatment

Burns are classified into 3 types:
1. Superficial burns (1st degree burns) - these are burns which are limited to the epidermis
2 Partial thickness burns (2nd degree burns)- this is subdivided into 2 types
2 a. Superficial partial thickness burns - these involve all of the epidermis and the upper layers of the dermis
2 .b Deep partial thickness burns - these involve the whole of the epidermis and dermis
3. Deep partial thickness burns (3 rd degree burns)- these involve all layers of the skin and subcutaneous fat

Treatment:
1st degree burns can be treated with lotions, honey, aloevera or topical antimicrobial.
2nd degree burns can be treated with either a topical antibiotic or an occlusive dressing.
3rd degree burns generally require a skin graft.

Cleaning  of burn wounds should be done with sterile water. Ice should not be applied to a burn wound as it may cause further damage due to hypoyhermia. Wound healing is expedited in moist environment therefore occlusive dressing is preferred. Silver sulphadiazine is the preferred topical antibiotic.

inhaled insulin: Afrezza

Insulin is typically available as subcutaneous or intravenous insulin for the treatment of diabetes.
First inhaled insulin which was approved was Exubera.

Exubera is a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed.  However a longer acting basal insulin by injection.

Exubera was however discontinued by Pfizer in 2007 due to poor sales as it was found that  though inhaled insulin appears to be as effective, but no better than injected short-acting insulin,  the additional cost was so much more that was unlikely to be cost-effective.

At the time of Exubera's discontinuation, several other companies were pursuing inhaled insulininsulin. Afrezza which belongs to Mankind pharma received FDA approval in June 2014

FDC Policy in India: Kokate Report

A FDC is a combination of two or more actives in a fixed ratio. Co packaged products are also treated as FDCs.

The need of Fixed dose combinations (FDCs) is increasingly being felt as they improve adherence to treatment or the combination of actives works synergistically.

The Kokate Report which is an Indian policy guidance on  approval of FDCS by CDSCO was released in June 2013.

As per the guidance for the approval of an FDC the following are a must:
1. Therapeutic rationalisation
2. Careful justification
3. Clinically relevant

The application for marketing authorization may comprise of
1. Original data
2. Data from literature
3. Hybrid: both original data and data from literature (most common)

However, quality data set will always be totally original

The SCOPE of the guidance is applicable to
1. import,
2. manufacture or
3. marketing approval of the FDC in India.


FDCs are classified into 4 main categories:

1. One or more active ingredients of the FDC is a new drug not approved india.

In this case FDC will be considered as an NCE and all requirements pertaining to an NCE will have to be fulfilled. Therefore a

Requirements will be as follows:
I. For phase I CT
1 .Data on  animal pharmacology and Animal toxicology
2.protocol of phase I trial.
3. IB
4 . ICD
5. Copy of ethics committee approval letters
6. Registration number of the ethics committee
7. CRF
8. Undertaking by the Investigator and CO
9. Undertaking by the sponsor

I I. For phase 2 CT
1. Summary of the non clinical data with references
2 . results of the repeat dose systemic toxicity studies to support the duration of proposed human exposure.
3. Study report of Phase I study.
4. Phase 2 study protocol
5. IB,ICD, CRF, Copy of EC approvals, registration numbers of the ECs,
6. Investigator and sponsor undertaking.

I I I. Phase  3 CTs
1. Summary of non clinical data
2. Study reports of phase 1 and phase 2 studies,
3. Protocol, IB, ICD, CRF of phase 3 trial, EC approvals and registration numbers.
4. Undertaking by sponsor and investigators.
5. Prescribing information of the drug circulated in other countries , if any.

IV. Phase IV TRIALS
1 . drug approval details and conditions for marketing
2. Proposed protocol, IB, ICD, CRF,EC approval letters,registration number of ECs
3. Undertaking by investigator and sponsor
4. Prescribing information, post marketing data of the FDC, clinical data generated post grant of marketing authorization.

Certain exceptions to this rule include:

1 a. If the individual APIs of the proposdd FDC are already marketed in another country which has a regulatory system comparable to india.
1b. The FDC is marketed in india however one of the API is not approved for the indication or in the strength as in the proposed FDC.
1c. FDC is already marketed in india but a change in ratio of the active ingredients is sought in the proposed FDC.

Principles of ICH GCP

Clinical research is mainly conducted world over on good clinical practice principles as outlined in the ICH GCP Guidance.

This is a tripartite guidance accepted by USA, Europe and Japan.

There are 13 principles outlined in the E6 guidance of ICH-GCP.ICH GCP is the international conference on harmonisation of technical requirements for registration of pharmaceutical products.The 13 principles are as follows:1. Clinical research based on ethical principles: Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s).2. Risk benefit analysis: Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks.3. Rights , safety and well being of subjects: The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society4. Adequate data to support study: The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.5. Clinical trials should be scientifically sound, and described in a clear, detailed protocol.6. Compliance to protocol:  trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favourable opinion7.Qualified physician: The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist.8. Qualification of individuals involved: Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).9. Informed consent: Freely given informed consent should be obtained from every subject prior to clinical trial participation10. Data collection: All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification.11. Confedentiality of records:The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).12. GMP: Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol. 13. Quality assurance: Systems with procedures that assure the quality of every aspect of the trial should be implemented.

Anti depressants

Major classes of antidepressants are:

1. SSRIs: Selective Serotonin Re uptake Inhibitors
Mechanism of Action (MOA): SSRIs prevent re uptake of serotonin in presynaptic nerve cells thereby increasing the concentration of serotonin in the synaptic cleft. Thus more serotonin is available to bind to post synaptic receptor. The SSRIs are:

a. Citalopram
b. Fluvoxamine
c. Escitalopram
d. Paroxetine
e. Sertaline
f. Fluoxetine


2. SNRIS : Serotonin Norepinephrine Re uptake Inhibitors
MOA: inhibit re uptake of serotonin and Norepinephrine. The drugs belonging to this class are:

a. Venlafaxine
b. Desvenlafaxine
c. Fluoxetine
d. Minlacipran
e. Levomilnacipran
f. Sibutramine

3. Atypical antidepressants
These antidepressants affect the neurotransmitters such as dopamine, Norepinephrine and serotonin.
a. Bupropion
b. Mirtazapine
c. Nefazodone
d. Trazodone

4. TCAs: Tricyclic antidepressants
a. Amitriptiline
b. Clomipramine
c. Imipramine
d. Desire mine
e. Nortriptyline

MOA: they mainly act by inhibiting re uptake of serotonin and Norepinephrine by blocking serotonin transporter

MAO I: Monoamine Oxidise Inhibitors
MOA: Act by inhibiting monoamine oxidase which breaks down neurotransmitters