Transcript The R&D process Clinical development_A.Gray

The R&D process
Clinical development
Andy Gray
Consultant pharmacist
3 basic objectives
• Demonstration of:
 Efficacy
• Does the drug work?
 Safety
• Is the drug safe to use, in the context of the
condition being treated?
 Quality
• Is the drug always going to work as predicted, in
that it will be delivered as promised in a suitable,
consistent dosage form?
http://www.treat-nmd.eu/userfiles/file/TACT_flowchart.pdf
Pre-clinical development
Pre-clinical development
• Objectives
 To sufficiently describe the reaction of various animals to the
drug, so as to identify major areas of concern
 ICH headings
• Carcinogenicity
• Genotoxicity
• Toxicokinetics and pharmacokinetics
• Toxicity
• Pharmacology
• Immunotoxicology
• The challenge – early identification of failure
6
Challenges for south-driven
innovation
• Deciding which pre-clinical investigations are really
needed and which may be superfluous
• ICH M3(R2): Guidance on Non-Clinical Safety Studies
for the Conduct of Human Clinical Trials and
Marketing Authorization for Pharmaceuticals
 Local variants?
 Ability of local regulatory authorities to authorise deviations from
global “norms”
• Capacity to undertake pre-clinical studies to GLP
standards
7
SA MRF1 directive
PART 4
PRE-CLINICAL STUDIES
a) Pre-clinical Expert Report
b) The following are results obtained and conclusions drawn from tests performed pre-clinically to
demonstrate all aspects of the toxicity of the medicine and to prove the safety of its use, with
special reference to (i)
acute toxicity;
(ii)
subacute toxicity studies;
(iii)
chronic toxicity studies;
(iv)
reproduction toxicity and teratogenicity studies;
(v)
carcinogenicity studies;
(vi)
mutagenicity studies; or
(vii)
other tests to substantiate the safety of the medicine; and
(viii) pharmacokinetic studies.
c) The methods and experimental results of, and the conclusions drawn from tests performed preclinically with reference to the efficacy of the medicine, with special emphasis on the relationship
between the tests performed and the purpose for which the medicine is, or will be used or for
which it will be propagated, and further, with regard to the dosage and method of administration of
the medicine, are as follows:
In cases concerning well-known active pharmaceutical ingredients, the Council may grant exemption
from the submission of some or all of the above information.
Clinical development
SA MRF1 directive
PART 5 CLINICAL STUDIES
a) Clinical Expert Report
b) The clinical trials performed on human volunteers and patients with regard
to the safety of the medicine, with special reference to the particular
dosage, routes of administration and the side effects observed, are as
follows:
c) The particulars of clinical trials conducted to establish the efficacy of the
medicine are as follows:
d) Experimental details and results of the studies performed to establish the
correlation between the applicable blood and other suitable physiological
levels, and the pharmacological action claimed for the medicine, are as
follows:
e) Periodic Safety Update Report for medicines for human use
10
Human pharmacology and PK
issues
• Examples of EMA guidelines




Pharmacokinetic Studies in man
Reporting the Results of Population Pharmacokinetic Analyses
Investigation of drug interactions
Evaluation of the Pharmacokinetics of Medicinal Products in
Patients with Impaired Hepatic Function
 Evaluation of the Pharmacokinetics of Medicinal Products in
Patients with Impaired Renal Function
11
Challenges for south-driven
innovation
• Interactions with medicines not commonly used
 Methadone
• When to investigate special populations
 Adolescents
 Post-menopausal women
 Pregnant and lactating women
• Emphasis on specific safety issues
 QT prolongation
• Capacity issues – as before
12
Clinical trials
INNOVATIVE DRUG DEVELOPMENT APPROACHES
FINAL REPORT FROM THE EMEA/CHMP-THINK-TANK
GROUP ON INNOVATIVE DRUG DEVELOPMENT
EMEA/127318/2007
• Communication issues
• Guidelines
• Biomarkers
• Statistical methods and clinical trial designs
• Faster access – conditional authorization
13
Challenges for south-driven
innovation
• Ability to access scientific advice/protocol
assistance from appropriate regulators
• “Rolling review” process
• A clear development pathway for follow-on products:
 Paediatric dosage forms
 New applications for drugs used already
 Fixed dose combinations
14
Next steps with 1% tenofovir gel
http://www.who.int/reproductivehealth/topics/rtis/WHO_UNAIDS_Next_steps_tenofovir_gel_Ex_report.pdf
•
•
•
•
•
•
Article 58 application to EMA
Additional safety studies
 young women aged 16‐17 years, women with hepatitis B infection and
women with impaired kidney function; safety in pregnancy
Confirmatory efficacy studies
 including younger women (aged 16‐30 years); and adding prevention of
HSV‐2 as a primary endpoint
Effectiveness and safety trial of simplified dosing and HIV testing
schedules
Effectiveness study
Treatment outcome and resistance study
 in those who seroconverted on gel
15
FDA pathway (Oct 2010)
•
•
“During the meeting, the FDA stated their preference for two wellcontrolled studies to verify the safety and efficacy of 1% tenofovir gel
prior to submission of a New Drug Application (NDA). The FDA furthermore
stated that the NIH-sponsored Phase IIB study, MTN-003, known as VOICE
(Vaginal and Oral Interventions to Control the Epidemic), represents a
second adequate and well-controlled study that would, if successful, serve
as the second pivotal trial together with CAPRISA 004 to support the
submission of an NDA for 1% tenofovir gel.”
“The agency agreed that the current preclinical program for 1% tenofovir gel
is sufficient to support a future NDA. However, they stated that additional
safety data on adolescents would be needed and that information on in
vivo drug interaction studies with commonly used vaginal products
should be obtained. Also, the FDA will ultimately need data on post
menopausal women. It was also agreed that a future meeting with the
FDA would be held to address any outstanding discussions associated with
product quality, including chemistry, manufacturing and controls (CMC).”
16
Summary
• Clinical development requirements stipulated by
medicines regulatory authorities are necessarily
stringent
• Finding an appropriate balance between access and
safety is not simple
• “Southern” regulators may not always be in a
position to offer advice, decide whether to deviate
from international “norms” (such as ICH), or conduct
“rolling reviews”
• The capacity to conduct pre-clinical and early phase
clinical studies in the “South” may be limited