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173
Investigational Drugs
Investigational New Drug Application
The investigational new drug application is the vehicle through which sponsors
formally make a request for approval of new drug for sale. Investigational new drug
(IND) application is the outcome of a successful preclinical clinical trials (human
trials).
The purpose of preclinical trial (animal pharmacology/toxicology testing) is to
develop adequate data to strengthen a conclusion that new drug is reasonably safe to
proceed for human trials. The pharmacological and therapeutic activity exhibited by
new drug candidate, is taken into account to justify its development for commercial
use for use in healthcare system. Once a product is identified as a viable candidate for
further development, the sponsor then focuses on collection of data and information
necessary to establish that the product will not expose humans to undesirable risks
when used in early-stage clinical studies.
The IND is not merely an application submitted to drug control administration,
seeking approval for marketing but also a request for allowing shipment of drug if
required. As per current law, drug should be approved before it is transported or
distributed across state borders. It is due to the fact that sponsor probably want to
ship the investigational drug to clinical investigators in several states, for which
permission is required from legal authority. Through investigational new drug
application, the sponsor technically obtains this exemption from the drug control
administration.
Types of Investigation Drug Applications
There are three types of applications:
• An investigator IND. It is submittedbyaphysician,whois responsiblefor both
initiatingandconductingclinicaltrialsonaninvestigationaldrug.Healsodirectly
supervisestheadministrationofdrugstothevolunteer(patient).
• Emergency use investigational drug application. It is considered by regulatory
drugauthoritytopermituseof an experimental druginanemergencysituation.
Itisalsousedforpatients,whodonotsatisfythecriteriaofanexistingstudyprotocol,
ornoneofapprovedstudyprotocolexist.
• Treatment investigational drug application. Itis submitted for experimental
drugs,showingpromisingusefulnessinseriousorimmediatelylife-threatening
conditionsinclinicalsetting.Thefinalclinicalresultisreviewedbydrugcontrol
administration.
Based on commercial reason, there are two investigational drug application
categories:
• Commercial
• Research(non-commercial)
Commercial investigational drug applications are submitted primarily by
manufacturers to get approval for new product to bring out in market. Research IND
(also called a non-commercial IND) submitted by the sponsor (generally an individual
investigator, academic institution or non-profit entity) does not have intention to
commercialize the product. The vast majority of INDs applications are noncommercial
research category. "Investigator INDs, Emergency Use INDs, and Treatment INDs are
also included in this category.
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Textbook of Pharmacy Practice
Generally, the data related to three areas as mentioned below are highlighted in the
application for investigational drug:
1. Pharmacological and toxicological studies: Preclinicaldata,concernedwithsafety
profileofdrugtoguidetheclinicalstudyforinitialtestinginhumans.
2. Information related to manufacturing of drug: The informationrelevantto the
composition,stability,andcontrolsusedformanufacturingthedrugsubstance/
drugproductareincluded.Thisinformationalsoprovidesabilityofcompanyto
producerequiredquantityandmaintainconsistentsupplyofinvestigationaldrug.
3. Clinical protocols and investigator information: This information providethe
details about protocols for proposed clinical studies toassess the possibility of
undesirablerisks,whendrugisusedinhumansubjectintheinitialphase.Also,
informationaboutthequalificationsofprincipalinvestigators(generallyphysicians),
whosupervisetheclinicaltrialoninvestigationaldrug.Theinvestigatorshouldbe
appropriatedqualifiedtosupervisetheclinicaltrial.
After submission of application for IND, the sponsor has to hold back the clinical
trial for 30 calendar days. During this time, drug regulatory authority get opportunity
to review the application IND for safety profile of drug.
Advisory Committee
The DCGI has twelve numbers of New Drug Advisory Committees (NDAC). These
committees have appointed experts to ensure clarity in approval of proposals for conduct
of clinical trials for drugs. Experts are professional from the government medical colleges
and eminent institutions from every part of nation. All fresh applications related to
clinical trial of new drug excluding investigational new drugs are reviewed by NDAC.
There are two and six separate expert committees for IND and for appraisal of medical
devices.
There are no specific provisions for regulating the conduct of clinical trials in Drugs
& Cosmetics Act, 1940, which also does not have penal provisions. Therefore, specific
provisions for this purpose are proposed in the Drugs & Cosmetics (Amendment)
Bill, 2007. This was presented in the Rajya Sabha on 21.8.2007. Later on, this bill
was replaced by the Drugs & Cosmetics (Amendment) Bill, 2013, introduced on
29.8.2013; consisting of more comprehensive provisions for the conduct of clinical
trials.
Newer Steps Taken by the CDSCO
DCG1 has issued direction in November 2013 to record the audio video of the informed
consent an individual subject, including the procedure of providing information to a
subject and his understanding of such content.
Another amendment is put forward in the schedule-Y specifying the requirement of
ethics committee in the institutions, where clinical trials are conducted.
It has been also been recommended that Investigator and institutional ethics committee
who is involved in conduct of clinical trials should be competent and institution, where
clinical trials are carried out should be accredited by a Central Accreditation Council
(CAC) to carry on such studies.
175
Investigational Drugs
EXERCISE
Multiple ChoiCe Questions
Tick mark the appropriate choice
1. Which is Investigational drug?
(a) Not approved
(b) Product approved for a new indication; or
(c) New drug in a new patient demographic form
(d) All of the above
2. What information IND application must contain?
(a) Preclinical data to ensure safety in human testing
(b) Manufacturing information
(c) Clinical protocols to analyze whether initial-phase trials pose any unnecessary risks to
research subjects.
(d) All of the above
short Questions
3. What is investigational drug? Discuss the principles followed in hospitals in the use of
investigational drugs.
4. Enumerate the guidelines for Institutions to develop investigational drug procedures.
long Questions
5. Discuss the principle implicated in the use of investigational drugs in hospital settings.
6. Discuss various types of investigation drug applications.
7. Discuss the role of pharmacist in the study of investigational drugs.
Answer to MCQs
1. (d) 2. (d)
176
Chapter
Interpretation of Clinical
Laboratory Tests
Various physiological parameters define the human health state. These parameters
are usually interconnected. Among various parameters, haemoglobin (Hb), complete
blood count (CBC), differential leucocyte count (DLC), urine tests are most important
and clinically significant.
The present chapter is compiled to give an overview of general laboratory diagnostic
tests used in clinical practice.
Blood Chemistry
Blood chemistry provides the understanding of chemical composition of the blood.
The measure of various components in the blood can give indications regarding
patient’s condition, ranging from the presence of a liver disorder to a pregnancy.
Routine blood analysis, which is often a part of a diagnostic work-up, explore blood
chemistry. The diagnosis, given by doctors, generally depends on information about
normal ranges of various components like blood cells, proteins, sugar and lipids
for blood analysis.
Various types of components are examined in test for blood chemistry. The basic
composition of the blood includes white blood cells, red blood cells, and platelets,
determined in routine blood test. In the haematocrit test (Hct), percentage of red blood
cells in the blood is determined. In blood examination, level of haemoglobin content,
the mean corpuscular volume, size of red blood cells, and the mean corpuscular
haemoglobin in a red blood cell are also examined.
Determination of level of specific enzymes like alkaline phosphatase, serum glutamic-
pyruvic transaminase (SGPT), and serum glutamic-oxaloacetic transaminase (SGOT)
can be helpful in determining the status of liver function. Presence of electrolytes like
sodium, potassium, chloride, and calcium can also be determined in a blood analysis,
along with levels of proteins and lipids. The level of electrolytes is determined to check
the imbalance in level of acid and base.
Specific blood tests can explore for nitrogen elements like blood urea nitrogen (BUN),
uric acid, and creatinine. These are useful for determining the proper kidney function.
Blood level of thyroid hormones can also be assessed to determine the functioning of
thyroid gland. In fasting blood sugar test, level of blood sugar is determined after an
overnight fasting to observe the signs of diabetes.
21
177
Interpretation of Clinical Laboratory Tests
BLOOD EXAMINATION/ HEMATOLOGICAL TEST
Following common tests are included in hematological tests to detect various blood
disorders:
1. Haemoglobin Value
Haemoglobin, present in red blood cells (RBCs) that transports oxygen from the lungs
to the various body’s tissues. It also aids in transport of carbon dioxide from the tissues
back to the lungs.
Haemoglobin is tetrameric protein comprises four subunits; Each unit has polypeptide
chain (as globulin chains) and one non-protein prosthetic ‘heme’ group. Alpha-globulin
chain (2 in numbers) and beta-globulin chain (2 in numbers) are present in haemoglobin
molecule in adult person. In foetuses and infants, haemoglobin molecule is devoid of
beta chain but contains alpha-globulin chain (2 in numbers) and gamma chains (2 in
numbers). T, the gamma chains are gradually eliminated as the infant grows, to give
the entry of beta chains. This replacement forms the same haemoglobin structure as
present in adult.
Iron is embedded within the ‘heme’ group, which is important to transport oxygen as
well as carbon dioxide in the blood as indicated above. The iron present in haemoglobin
is also answerable for the red colour of blood.
Haemoglobin is also an important for maintaining the shape of the RBCs. Red cells are
distinguished by flattish, doughnut-like shape (without a hole) that allows them to perform
their functions effectively. The abnormalcy, if any, in haemoglobin structure changes the
shape of red blood cells, which hamper their functions and flows through blood vessels.
The haemoglobin
level is indicated as the
haemoglobin content
(in g) per decilitre (dL or
100 ml) of whole blood.
The normal range for
haemoglobin varies
depending on age and,
gender, as indicated here:
Clinical Importance
• LowhaemoglobinlevelconditionisascribedasanemiaordecreasedRBCs.Several
reasonsmay be ascribed for anemia.Common reasonsare lossof blood (due to
traumaticinjury,surgery,bleeding,cancerorulcerationinstomach),deficiencyof
nutrients(iron,vitaminB
12
,folate),problemsrelatedtobonemarrow(bonemarrow
cancer),suppressionofbonemarrowbycancerchemotherapy,chronickidneydisease
(CKD),andabnormalityinhaemoglobinstructure(sicklecellanemiaorthalassemia).
Thalassemiaisaninheritedblooddisorder,inwhichthebodymakesanabnormal
haemoglobin,responsibletotransportsoxygen.Thistypeofdisordercausesexcessive
destructionofredbloodcells,whichleadstoanemia.
• Haemoglobinlevels,higherthannormallevelarereportedinpeople,residinginhilly
areaandwhoenjoysmoking.Falsehighhaemoglobinvalueisobservedindehydration
condition,butbecomenormalonrestorageofproperfluidbalance.
Age/gender Hb content
Recently born baby 14.6–25.6 g/dL
7 days 15.5–20.5 g/dL
30 days 11.5–15.5 g/dL
Children 11.5–13.5 g/dL
Adult males 14.5–18.5 g/dL
Adult females 12.5–16.5 g/dL
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Textbook of Pharmacy Practice
Other infrequent causes are:
• Advancedpulmonarydisease,e.g.emphysema,COPD
• Certainmalignantcondition
• Bonemarrowdisorder,e.g.polycythaemiarubravera
• Abuse ofthe drug,like intakeof erythropoietin (Epogen)by athletesto enhance
performance.
2. Cell Counts
There are three types of blood cells:
i. Redbloodcells(RBCs)
ii. Whitebloodcells(WBCs)
iii. Platelets
These are expressed as number of cells per cubic millimetre.
i. Red Blood Cell (RBC) Count
The RBCs contain haemoglobin, which imparts the red colour to blood. Bone marrow
of bones produces the RBCs.
There is lower RBC count in female
in comparison to male, and the RBCs
count tends to decrease with age.
Normal range is indicated in the form
of their number as:
Clinical importance: RBC count is a part of a CBC test and included in a health check-
up programme to screen for a variety of conditions. This test may also be used to
diagnose and/or monitor any disease that affect the production or lifespan of the RBCs.
Increased RBCs number above normal range suggests the presence of heart ailment,
polycythaemia, and cholera while decreased number indicates the development of
anemia.
Some reasons of a low RBC count include:
• Traumaticcondition.
• DestructionofRBCs,forexample,inhaemolyticanemiacausedbyautoimmunity
ordefects in thered cellitself; sickle cell anemia, thalassemia, or premature
destructiondue to enzyme defect (e.g.,glucose-6-phosphate dehydrogenase
deficiency).
• Bleeding (acuteor chronic)in thedigestive tract(e.g. ulcerativeconditions, cyst,
cancerofcolon)orothersites,suchasthebladderoruterus.
• Insufficiencyofnutrients(e.g.iron,orvitaminB
12
orfolate).
• Bone marrowimpairment (may be caused bytoxin, radiation or chemotherapy,
infection,drugs).
• Bone marrow disorders like leukaemia, lymphoma, multiple myeloma,
myelodysplasia,orothercancersthatspreadtothemarrow.
• Chronicinflammatoryconditions.
• Renal failure:Lead to decreased productionof erythropoietin (hormone)by the
kidneysthatstimulatesRBCformationbythebonemarrow.
Gender/age million/mm
3
Male 4.5–6.0
Female 4.5–5.5
Children 3.8–5.2
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Interpretation of Clinical Laboratory Tests
Some reasons for an increased RBCs count (polycythaemia) include:
• Polycythaemiavera(inappropriately,increasedproductionofRBCs).
• Pulmonaryfibrosis(scarringofthelungs)
• Congenitalheartdisease(angina,CHF,ischemicheartdisease,myocardialinfarction,
etc).
• Kidneytumourthatreleasesmorequantityoferythropoietin.
• Chronicsmoking
• Lossofsaltandwater(forexample,
diarrhoea)
Haematocrit (Hct) value: Itindicates
thepercentageofRBCsinthebloodin
body.Forexample,a25%haematocrit
valuemeans,25mlofRBCsin100ml
ofblood.
It varies depending on age and sex
of the individual.:
Clinical importance: Decreasedhaematocritvalueindicatesthedevelopmentofanemia.
Therearemanyreasonsforanemia.Someofthemorecommonreasonsare:
i. Lossofblood(e.g.traumaticinjury,surgery,bleeding,andcancerofcolon).
ii. Insufficiencyofnutrients(iron,vitaminB
12
,folate).
iii.Bone marrow complications (cancerous bonemarrow bycancer,repressionby
chemotherapydrugs,nephrotoxicity),and
iv. Defectivehaemoglobin(e.g.sicklecellanemia).
High haematocrit value represents increased RBCs count. High haematocrit value
can be observed in people, who live in hilly areas and are chronic smokers. False high
haematocrit is observed in dehydration, that is restored with intake of fluid. Pulmonary
disease, certain carcinomas, polycythaemia rubra vera, abuse of the drug erythropoietin
(Epogen) as illustrated above are some other causes of high haematocrit value.
Mean corpuscular volume (MCV): ItisapartofCBCtest,whichmeasuretheaverage
RBCsizeandvolumeofRBCsinaspecimenofblood.MCVisincreasedordecreased
dependingon average redcell size; forexample, lowMCV, normaland highMCV
designate microcytic anemia (small average RBCsize), normocytic anemia (normal
averageRBCsize),andmacrocyticanemia(largeaverageRBCsize).Meancorpuscular
volume(MCV)istheaveragevolume of red cells. MCV canbedirectlydetermined
withtheuseofautomatedanalyser,oritcanbedeterminedbymultiplyingthepercent
haemaocritbytendividedbytheerythrocytecount.
MCV = Haematocrit (%) × 10 ÷ RBC count
MCV, along with mean corpuscular haemoglobin (MCH), and mean corpuscular
haemoglobin concentration (MCHC), is a part of erythrocyte indices or RBC indices.
RBC indices measure the size, shape, and quality of the red blood cells.
Normal reference range for MCV in adult person varies from 80 to 94 fL/red cell. It
also depends on the individual laboratory and age of person.
Mean corpuscular haemoglobin concentration (MCHC):ItisapartofCBCtest,which
measuresthehaemoglobinconcentrationinagivenvolumeofpackedredbloodcells.
Age/gender % Hct
Recently born baby 55–69
7 days 47–66
30 days 37–50
One year 29–42
Ten years 36–42
Male(adult) 38–54
Female (adult) 36–47
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Textbook of Pharmacy Practice
OndividingthehaemoglobinvaluebythehaematocritvaluegivestheMCHCvalue.
MCHC (g/dl) = hamoglobin ÷ hamatocrit.
Normal value for MCHC is 34 ± 2 g/dl for adult person
Red cell distribution width (RDW): It is a part of CBC test,which measures
unpredictabilityin redcell volume/ size (anisocytosis).Normal RDWmeans, red
bloodcellsaresimilarinsize.Generally,anormalRDWrangesfrom12%to15%,but
thisnumber may vary depending onthe individual laboratory and age of person.
NormalRBChasastandardsizeof6to8µmindiameterbutRDWiselevatedifthe
rangeofsizesbecomeslarge.
ii. Total White Blood Cell (WBC)
WBCs, also called leucocytes, are colourless and nucleated cells. They are bigger in
size than RBC but lesser in number. White blood cells are the fighter cells of the body
immune system. They protect against infections by fighting against the foreign invaders,
like bacteria and viruses. They are made in the bone marrow and stored in blood and
lymph tissues. These are uneven in shape and devoid of haemoglobin. They have a
short lifespan, usually 15 to 20 days. WBCs count is considered an important criterion
to diagnose various diseases, e.g. autoimmune and inflammatory diseases, in which
body immune system attack healthy tissues.
Total leukocyte count (TLC) varies from 5000 to 11000 per cubic millimetre but
8000 per mm
3
is a normal average value.
Clinical importance: TheelevatedWBCscountiscalledleukocytosis,whichismost
commonlycaused by infection or inflammation. Other reasonsfor elevatedWBCs
countmayinclude:
• Severephysicaloremotionalstress(suchasfever,injuryorsurgery).
• Burns.
• Disordersrelatedtoimmunesystem,suchasrheumatoidarthritis.
• Thyroidcomplications.
• Dentalcaries.
• Certainmedicines,likecorticosteroidsandbeta-agonists.
• Allergies.
• Removalofspleen.
• Smoking.
• Obesity.
• FinalstagesofpregnancymaybeassociatedwithincreasedWBCscount.
DecreasedWBCsareknownasleucopoenia.Itisduetosomeconditionssuchas:
• Bonemarrowinjury(e.g.toxin,chemotherapy,radiationtherapy,drugs).
• Bonemarrowcomplaints,inwhichbonemarrowdoesnotproducesufficientWBCs
(e.g.myelodysplasticsyndrome,vitaminB
12
orfolatedeficiency).
• Lymphomaorothercancerthathasspread(metastasized)tothebonemarrow.
• Autoimmune disorders,in which body attacks anddestroys itsown WBCs (e.g.
lupus).
• Overwhelminginfections(e.g.sepsis).
181
Interpretation of Clinical Laboratory Tests
• Diseases, in which the immunesystem isaffected, maybe dueto destructionof
Tlymphocytes,suchasHIVdisease.
iii. Differential Leukocyte Count (DLC)
WBCs provide a frontline defence against different diseases. Two types of WBCs
(granulocytes and agranulocytes) are present in the blood. Granules or sacs are present
in cytoplasm, while agranulocytes do not have granules.
Granulocytes: Basophils, neutrophils, and eosinophils
Agranulocytes: Lymphocytes and monocytes
Monocytes are the phagocytes, that protect the body by ingesting foreign invaders.
DLC (differential leukocyte count) test determines the percentage of different types of
granulocytes as well as agranulocytes. The normal ranges for percentage of granulocytes
and agranulocytes are illustrated below.
Type of cell percentage Absolute count (per mm
3
) Significance
Neutrophils 50–70 2,500–6,000 Increased and decreased percentage of
neutrophils in blood is called neutrophilia
and neutropenia respectively.
Basophils 0.0–1 0–100 Elevated percentage of it is called basophilia.
Eosinophils 1–3 50–300 Increased percentage of eosinophils is called
eosinophilia.
Monocytes 4–6 200–800 Increase in its percentage is called monocytosis.
Lymphocytes 25–35 1,100–4,000 Increase in percentage of lymphocytes in the
blood is called lymphocytosis and decrease
in lymphocytes below normal is called
lymphocytopenia.
Each type of white blood cell has its own unique features.
Clinical significance: Both TLC and DLC are supportive in detecting infectious
disease.
• Neutrophils,mostcommonoftheWBCs,areimportantpartoftheimmunesystem
thathelpsthebodyinfightingagainstinfection.Inresponsetoinfectionorserious
injury, level of neutrophils becomes high. Hence,a high neutrophil count isan
indicationofsevereinfection.
• Eosinophilsprovideprotectiontothebodyfromparasites,allergens,foreignbacteria,
etc.Hence,elevationsineosinophilcountsareassociatedwith:
± Hypersensitivityreactions
± Infectionsduetoparasites
± Long-termskininfections
± Somecarcinomas
• Basophilsleveliselevatedingranulocyticleukaemia.
• Lymphocytesplayanimportantroleintheimmunesystem,throughwhichbodyfight
againsttheinfection.lymphocytosisisahighcountoflymphocytesinblood.Increased
countoflymphocytesisobservedinhepatitis,herpessimplex,herpeszoster,syphilis,
whoopingcough,tuberculosis,leukaemia,etc.Lymphopeniaislowlymphocytecount,
whichresultsduetoacuteinfections,burns,trauma,lupus,HIV,andlymphoma.
• Monocytesincreaseinbacterialinfection/malariaandmonocyticleukaemia.
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Textbook of Pharmacy Practice
iv. Platelet or Thrombocyte Count
Platelets are cell with irregularly shape, and devoid of nucleus. It is typically only
2–3 µm in diameter. Platelets play an important role in wound healing, and blood
clotting. Platelet counts are usually done by laboratory machines that also count other
blood components such as the WBCs, and RBCs. Counting can also be done with the
use of a microscope in the laboratory.
The 150,000 to 400,000 per µm (or 150–400 × 10
9
per litre) is a normal platelet count.
Thrombocytosis is a condition, in which level of platelets is increased more than 450,000
while in thrombocytopenia level becomes less than 150,000. Both thrombocytopenia and
thrombocytosis can cause complications in process of blood coagulation. Platelet count
below 50,000 or above 1,000,000 is considered as crucial. In case of high value, blood
clotting is encouraged in blood vessels, blocking the blood supply to heart and brain.
The low count, especially below 20,000, may cause spontaneous bleeding, which is a
life-threatening situation.
3. Erythrocyte Sedimentation Rate
Erythrocyte sedimentation rate (ESR) test or sedimentation rate test, evaluates the speed
at which whole blood cells descend standardized glass tube over a period of one hour. It
is expressed as the fall of RBCs in mm at the end of first hour. ESR can help to diagnose
or monitor the progress of an inflammatory disease. Inflammation can cause the cells
to clump, which are denser than individual cells. Hence, they settle to the bottom more
quickly and thus give faster ESR rate.
NormalvalueforESR
a. ByWestergren’smethod:
–Adultmale:0–5mmafterthefirsthour.
–Adultfemale:0–7mmafterthefirsthour.
b. ByWintrobe’smethod:
–Adultmale0–9mmafterthefirsthour.
–Adultfemale0–20mmafterthefirsthour.
Clinical importance: The ESR is a non-specific signal, helpful in the diagnosis and
monitoring of inflammatory diseases. It indicates mainly the increase in formation of
a certain protein, generated in response to inflammation. These are developed in many
acute and chronic infections, cancers and degenerative autoimmune disorders such as
rheumatoid arthritis.
Although, a low ESR value is not so significant but can be observed in erythrocytosis,
(means high concentration of red blood cells in blood), and with some protein
abnormalities. Some changes in red cell shape (such as sickle cells in sickle cell anemia)
are also responsible for low ESR value.
4. Coagulation Time/Clotting Time of Blood
Clotting time is the time taken by a sample of blood to coagulate in vitro under
standard conditions. It is actually measurement of the intrinsic power of the blood to
convert fibrinogen to fibrin. Normal ranges in capillary and venous blood methods
are: