FDA Drug Review Process: A Case Study of TVEC for Melanoma Treatment

Desklib provides past papers and solved assignments for students. This report details the FDA drug review process for a melanoma treatment.

Contents
INITIAL PHASE FOR DRUG DEVELOPMENT.................................................................................1
GENERAL INFORMATION REGARDING THE DRUG (T VEC) Imlygic..........................................1
FDA REVIEW FOR DRUG TVEC.................................................................................................1
STAGES OF FDA DRUG REVIEW...............................................................................................1
JUSTIFICATION........................................................................................................................3
DETERMINATION OF SAFETY AND EFFECTVENESS OF DRUG TVEC............................................4
SAFETY.................................................................................................................................... 4
EFFECTIVENESS.......................................................................................................................4
CLINICAL TRIAL EXPERIENE.....................................................................................................4
LISTING AND MEETING OBLIGATIONS FOR FDA.........................................................................5
FDA REVIEW TYPE...................................................................................................................6
LEARNING OUTCOMES FROM THE EXCERCISE...........................................................................7
REFERENCES............................................................................................................................... 7
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INITIAL PHASE FOR DRG DEVELOPMENT
GENERAL INFORMATION REGARDING THE DRUG (T VEC)Imlygic
Cancer is a life threatening condition and most prevalent in current times. Several therapies for
cancer is developed some have good rate of effectiveness and other do not. Overall the cancer
is a disease that cannot be cured or eradicated. Melanoma being the commonest form of skin
cancer and most prevalent cancer in UK needs better pharmacological treatments than present.
It is estimated that around 1 in 10 people in UK are diagnosed of melanoma in later stages of
disease. It is also estimated that he rates of melanoma prevalence in UK will rise for about 7%
till 2035 with rate of 35 people diagnosed every 100,000 people in UK (Conry, Westbrook,
McKee and Norwood, 2018).TVEC is the new multidrug therapy regime that has proved to be
more effective in cancer cure than other drugs. It is not a drug metabolite but it is a derived
virus that kills the cancer cells in the body leaving the healthy cells unharmed. T VEC is an
oncolytic virus that is administered to the site of cancer that targets the cancer cells and kills it.
It is made up from genetically modified herpes virus cells. Cancer cells are prone to get resistant
to drugs and can overcome the exiting drug regimens but the viral attack is not resistible by
these cells making the drug effective in cancer cure (Greig, 2016.)The drug is developed to
modify the cancer physiology by killing the cells and enhancing the immune system response in
the body.
FDA REVIEW FOR DRUG TVEC
Whenever a new drug is developed or is introduced and its efficacy has to be evaluated through
trials and experimentation the role is FDA is crucial in this process. FDA stands for Food and
Drug Administration that is an association which is responsible for approval of safe and legal
drug use of ay drug and its marketing in the health and social care system. The journey of any
drug from the laboratory desks to the counter of a medical store is not easy as well it has to
pass through various stages of FDAA approval and consent (Hazarika, White, Johnson and
Pazdur, 2004). FDA approval systems keenly observe the development of drugs during its stages
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of development as well as speculate the effect of drugs on the human subjects and its
effectiveness and harmfulness on human being.Center or Drug Evaluation and Research (CDER)
is the association that works with FDA to provide evidence regarding the efficacy and
effectiveness of any drug and makes the approval process easier for the FDA.
STAGES OF FDA DRUG REVIEW
1) STANDARD TREATMENT AVIALBLE FOR THE DISEASE IN THE MARKET
 The most common form of treatment available for melanoma in market is the
combination chemotherapy with or without additional radiotherapy.
 Lymphatic mapping and lymph node dissection for metastatic melanoma
 Dacarbazine is the only most widely used chemotherapy drug to treat melanoma that s
approved by FDA (Mann etal, 2007).
 External beam radiation therapy with specific radiation regime
 Stage III and IV melanoma cannot be treated by radiotherapy and requires adjuvant
chemotherapy or pharmacotherapy to be cured
Most of the treatment options that are currently available in the market to cure melanoma has
some side effects or are not appropriate to treat stage III or stage IV melanoma. The common
side effects of radiotherapy involve skin irritation, fatigue; immunotherapy causes flu like
symptoms, fever, chills, nausea, diarrhea, rashes, hair thinning, depression etc. TVEC is the
genetically modified virus therapy that includes administration of virus in the body that does
not play any role in harming the healthy cells of the body and only targets the cancer
cells(Schvartsman et al, 2017). It has relatively less harmful side effects than other drugs and is
a substance that has higher efficacy in achieving cancer eradication.Suffering of the patient is
comparatively less than in other therapies used for the treatment of melanoma. By presenting
all the facts and information regarding the drug I would request my sponsor to convince the
FDA to approve the drug for clinical trial and the review process.
2) INVESTIGATIONAL NEW DRUG APPLICTION
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The actual role of FDAA in the review of any new drug starts when the developer of drug has
developed a new pharmacological substance that is effective in treating a specific disease and
also has experimented with the preclinical trials of toxicity on animals. After this the next step
the company takes is to start a clinical trial on human subjects to ensure the efficacy and
effectiveness of drugs. This step involves submission of a form by the drug developer to the FDA
that is known as Investigational New Drug Application. The process includes the sponsor
showing the results of preclinical trials to the FDA and IRB that is Institutional Review Board.
The results and the application is thoroughly scanned by the members of FDA and IRB
(Institutional Review bBoard) and minute details like informed consent forms of participants,
associated harmful effects of drug and its review all these things are analyzed by the boards
before approving the drug for clinical trial. IRB also ensures the participants know the process
and risk associated with the trial and also makes sure the drug developer takes care of
confidentiality and safety of the subjects involved (Bayer et al, 2017).
3) PHASES OF CLINICAL TRIAL
Phase I testing
The phase I of clinical trial initiates after the approval from the FDA. This phase includes
participation of relatively small number of sample that is not more than 20 to 80 participants.
This phase is characterized by administering small amount of drug to the individuals suffering
from the disease to be treated and monitoring them for days or weeks for any harmful effect or
effectiveness. Aim of this phase is to study the metabolism and excretion of drug in human
beings (Goldufsky et al, 2013).
Phase II testing
Phase II aims at providing evidence for the efficacy of the drug in human being. It is processed
only when the phase I results do not indicate any amount of toxicity or harmful effects. The
sample size in this phase is around 300 people. The drug is administered and monitored for
weeks or months to identify the extent of effectiveness it has on curing the disease.
Phase III testing
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After the drug passes phase II and no toxicity over a considerate dosage or any other harmful
effects are seen it is passed through phase III. This phase measures the effectiveness and
efficacy of the drug in comparison to other drugs and its effects on human physiology. The
number of sample ranges to about 3000 people and the study involves different population on
randomized control trial basis (Grimaldi,Marincola, and Ascierto, 2016).
Phase IV testing
After the drug has confirmed its efficiency in phase III it is approved by FDA to be marketed in
the market and sold out for the treatment of disease. This phase is done after the approval and
to ensure the long term effects of the drug on human. It takes years to analyze the effects of
new drug versus the old ones available in the market and to determine the effectiveness
efficiency of this drug in reducing the disease or curing it over old regime. Sample size is far
larger than phase 3 and pharmacovigilance is started as soon as the drug is out in the market
and adverse evenst are reportd to the sponsorsThe sample size is large taken by randomized
control sampling and the participants are given different drugs without any notification and the
results are analyzed without bias.
NDA application is applied after phase 3 and relatedor IND that is investigational new drug
application meetings can be held after the testing or during the clinical trial is on. These
meetings are held to get complete approval and ensure the FDA about safe and healthy
procedures of trial. The results of the drug testing in every phase are also presented in front of
FDA in these meetings to get approval for another phase of trial. After the three phases of trial
complete marketing approval is gained by the FDA (Sullivan and Flaherty, 2015).
JUSTIFICATION
The FDA has provided lengthy yet simple steps to be followed to investigate and get new drug
approved. No aspect of drug review leads to any error or misconduct of the drug during trial as
well as allows keen observation of the safety and effects of drug on the human beings. This
procedure is simple and allows the company to follow a guided path in order to get the
approval from FDA. Investigational new Drug Application is a good way to submit the form
regarding new drug introduction and the approval of the form makes the drug go through other
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stages of the review. If the developer presents the main criteria how their drug is better to
preexisting treatments for the disease this makes it feasible to convince FDA better.
DETERMINATION OF SAFETY AND EFFECTVENESS OF DRUG TVEC
SAFETY
Whenever the drug is developed the safety of the substances used in the drug ad treatment
regime is most important concern and main criteria for approval from FDA. To ensure the safety
of drug over human beings first preclinical trials are done in animals and if there is no toxicity
seen the results of these trial are presented to FDA to get approval for clinical trials. Phase I, II,
III testing in clinical trial is also done to ensure safety.
TVEC may cause some side effects that are as follows
 Fatigue, nausea, fever, chills nausea
 Vomiting, diarrhea, constipation
 Abdominal pain, injection site pain, headache
 Weight loss, dizziness, throat pain (John and Cowey, 2015)
All these facts are gathered from the preclinical and clinical trials done to ensure safety of TVEC.
EFFECTIVENESS
The effectiveness of the drug is referred to the successful results of drug achieved by its
intended use in particular population suffering from the disease to be treated. The
effectiveness of drug is ensured by the clinical trial where the effectiveness is measured in
phase II and III by qualitative and quantitative analyses of the drug. The effectiveness of the
drug TVEC is determined by the randomized control trial by Perez et al, (2018). The study shows
the observation and monitoring of 27 melanoma patients who were treated with the drug TVEC
(John and Cowey, 2015). Out of 27 patient 25 of them showed very good control over the
disease with the use of this drug and following the ten week follow up. The rate of control of
disease was 78.3%. This proved that TVEC is well tolerated and intralesional therapy that only
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target the lesion cells and do not harm the healthy tissues. It is found to be effective for the
patient with higher grade melanoma of stage III and IV. These findings reveal our drug to be
considerably safe and effective to treat melanoma in human.
CLINICAL TRIAL EXPERIENE
The phase I trial for TVEC was done with 30 participants to determine the safety and efficacy of
drug to treat melanoma. The trial consists of single dose of injected drug and multi dose of
initial low virus injected to the patient.The most severe side effect found in the trial was pyrexia
with some participantsexperienced pain at the administration site. Keeping n consideration the
results of phase I trial the phase II testing was conducted taking 50 patients. The phase II trial
included 50 patients with stage III and IV melanomas where surgery was no more indicated. The
testing consisted of six injections of TVEC to the patient and 85% of patients experienced
adverse flu like symptoms. The 23% response was achieved where 8 patients received complete
response from drug and 5 patientsachieved partial response (Sloot, Rashid and Zager,
2014.)The anti-tumor immunity was seen patients who achieved full response with increased
CD4 cells in their body. The phase III study for TVEC was one of the kinds as it was first phase III
study for any oncolytic virus drug. In this phase TVEC was compared with GM CSF recombinant
treatment for melanoma. Total 436 patients participated out of which 43% had stage III cancer
and 53% received prior systemic therapy. The result showed that DRR was higher in TVEC
sample than GM CSF population. Also the median survival rate in TVEC arm was 23.3 months as
compared to GM CSF arm that is 18.9 months. The adverse events that occurred in this phase
were only pyrexia, chills, nausea and omitting whereas 2% of adverse effect appeared to be
cellulitis. Based on these findings TVEC can be approved by FDA.
LISTING AND MEETING OBLIGATIONS FOR FDA
1) IND application submission meeting
The foremost interaction with the FDA is done at this meeting where sponsor of the drug
presets the proposal in form of new drug investigation application to FDA. The application is
submitted to FDA and it requires the attachment of results from preclinical trial and all the
consent forms and details of the participants for clinical trial. FDA takes around 60 days to
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revert back to the application. The approval can be given to the drug for clinical trial after
assessing all the safety aspects and if there are some loop holes present than the trial can be
put on hold or can be partially approved with some guidelines to be followed. The
pharmacokinetics, dosage and pharmacology of drug are analyzed here (Franklin et al, 2017).
2) Phase I report (safety reporting obligation)
The safety report is to be submitted at this meeting where the phase I report with clinical,
preclinical and invitro study report is submitted t FDA. Any adverse or harmful reaction
identified has to be reported to FDA less than 7 days of identification. FDA analyzes the safety
of drug to approve other steps of review. It will take FDA 60 days or more to approve the other
stage and analyze the safety report properly.
3) End of phase II meeting
The end of phase I testing indicated a meeting between sponsor and FDA where the detailed
report of phase I is submitted to the FDA where the safety, effectiveness, dosage,
pharmacokinetic etc. is discussed giving evidence from results of previous phase. Other than
this at the end of phase II testing the again the report is submitted and the clinical implication
of safety and toxicity of drug is observed for the efficiency in phase III testing. If the drug is
found fit to pass phase III trial it is approved by FDA for phase III. The relevant regulatory
requirements are observed and the activities are developed in order to it (Gozalo‐Marcilla et al,
2018).
4) Phase III reporting
Phase III testing requires years of observation and monitoring and as the annual report for
phase III should also be submitted. While the NDA meeting is done the preclinical results can be
backed to achieve the marketing approval after phase III testing. These meetings help in
resolving issues, convince the FDA for approval, and to produce general and technical
information related to review.
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FDA REVIEW TYPE
The FDA review can be either standard or priority type based on the time taken for the review
process. Standard review takes 12 months from the date of submission whereas priority review
taken 8 months from the submission of IND. The type of review is not based on the drug
developer or sponsor or any other criteria but the sponsor presenting details about the
effectiveness of drug over the preexisting drug regime for the treatment of indicated disease is
the criteria that determines the type of review. FDA ensures that the drugs that is promising
better results than preexisting treatment should be reviewed faster and marketed for better
effects (Perez et al, 2018).
DRUG LABEL / PACKAGE INSERT
Package insert is the printed sip that is attached to the drug while manufacturing and is
marketed with it to produce indication for use and it provides help to the professionals for
prescribing the drug.
a) DOSAGE AND ADMINSTRATION
Administer TVEC with injection into cutaneous, subcutaneous or nodal lesion
Recommended starting dose is upto 4ml at concentration of 10◦ (1 million) plaque forming
units
b) INDICATION
TEC is genetically modified oncolytic viral therapy indicated for local treatment of unresectable
cutaneous, subcutaneous, nodal melanomas.
c) WARNING AND PRECAUTIONS
 Accidental exposure to the drug will cause exposure to herpes viral antigen. It will cause
herpes virus infection, healthcare professionals and others should avoid close contact to
the lesion and the drug. In case of accidental exposure clean the affected area.
 Herpetic infection
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 Injection site inflammation and pain
 Immune mediated events
d) CONTRAINDICATIONS
Immunosuppressant patients
Pregnant women
e) SIDE EFFECTS
Chills, fever, nausea, vomiting, diarrhea, fatigue, flu like symptoms
To report SUSPECTED ADVERSE REACTIONS, contact 1-855-IMLYGIC (1-855-465-9442) or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
LEARNING OUTCOMES FROM THE EXCERCISE
1) This exercise helped in learning different aspects of a drug review. It helped in understanding
the step wise procedure for the review process of new drugs including Investigational new drug
application submission to the approval of drugs by reporting the results of clinical trials. The
assignment helped me to understand how the drug is being reviewed by FDA and the
importance of reviewing a drug for safe marketing and usage in health and social care. After
reading all about FDA drug review procedure and the concepts of attending meetings for FDA
approval it made me particularly develop my skills regarding the practice and the process. I also
learnt the need for clinical trials and the process of clinical trials. The procedure of preclinical
and clinical trial helps analyzing the efficacy and safety of drug as well as its effectiveness (John
and Cowey, 2015).
I also learnt about the limitations of the process and the challenges a sponsor or developer
faces during the whole process of drug review. The documentation required for the review
process and the task of meetings and finding best sponsor to represent the drug is crucial.
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2) the main and most important criteria that the new drug can be prioritized in the review
process is to present how our drug is better and more effectivein treating the intended disease
than already existing treatment modalities. I also learnt what are the issues that can led the
trail to suffer and to ensure proper consent of the participants as well as reporting of the results
after each phase of the testing to convince and gather the support of board members. Above all
it is seen that the most effective and safe drugs can only pass through phase II and can be
approved after the results gained from phase III trials (Perez et al, 2018).
REFERENCES
1. Bayer, V., Amaya, B., Baniewicz, D., Callahan, C., Marsh, L. and McCoy, A.S., 2017.
Cancer Immunotherapy: An evidence-based overview and implications for
practice. Clinical journal of oncology nursing, 21.
2. Conry, R.M., Westbrook, B., McKee, S. and Norwood, T.G., 2018.
Talimogenelaherparepvec: First in class oncolytic virotherapy. Human vaccines
&immunotherapeutics, 14(4), pp.839-846.
3. Franklin, C., Livingstone, E., Roesch, A., Schilling, B. and Schadendorf, D., 2017.
Immunotherapy in melanoma: recent advances and future directions. European Journal
of Surgical Oncology (EJSO), 43(3), pp.604-611.
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4. Goldufsky, J., Sivendran, S., Harcharik, S., Pan, M., Bernardo, S., Stern, R.H., Friedlander,
P., Ruby, C.E., Saenger, Y. and Kaufman, H.L., 2013. Oncolytic virus therapy for
cancer. Oncolytic virotherapy, 2, p.31.
5. Gozalo‐Marcilla, M., Gasthuys, F., Luna, S.P.L. and Schauvliege, S., 2018. Is there a place
for dexmedetomidine in equine anaesthesia and analgesia? A systematic review (2005–
2017). Journal of veterinary pharmacology and therapeutics, 41(2), pp.205-217.
6. Greig, S.L., 2016. Talimogenelaherparepvec: first global approval. Drugs, 76(1), pp.147-
154.
7. Grimaldi, A.M., Marincola, F.M. and Ascierto, P.A., 2016. Single versus combination
immunotherapy drug treatment in melanoma. Expert opinion on biological
therapy, 16(4), pp.433-441.
8. Hazarika, M., White, R.M., Johnson, J.R. and Pazdur, R., 2004. FDA drug approval
summaries: pemetrexed (Alimta®). The oncologist, 9(5), pp.482-488.
9. John, L. and Cowey, C.L., 2015. The rapid emergence of novel therapeutics in advanced
malignant melanoma. Dermatology and therapy, 5(3), pp.151-169.
10. Mann, B.S., Johnson, J.R., Cohen, M.H., Justice, R. and Pazdur, R., 2007. FDA approval
summary: vorinostat for treatment of advanced primary cutaneous T-cell
lymphoma. The oncologist, 12(10), pp.1247-1252.
11. Perez, M.C., Miura, J.T., Naqvi, S.M.H., Kim, Y., Holstein, A., Lee, D., Sarnaik, A.A. and
Zager, J.S., 2018. TalimogeneLaherparepvec (TVEC) for the Treatment of Advanced
Melanoma: A Single-Institution Experience. Annals of surgical oncology, 25(13),
pp.3960-3965.
12. Schvartsman, G., Perez, K., Flynn, J.E., Myers, J.N. and Tawbi, H., 2017. Safe and effective
administration of T-VEC in a patient with heart transplantation and recurrent locally
advanced melanoma. Journal for immunotherapy of cancer, 5(1), p.45.
13. Sloot, S., Rashid, O.M. and Zager, J.S., 2014. Intralesional therapy for metastatic
melanoma. Expert opinion on pharmacotherapy, 15(18), pp.2629-2639.
14. Sullivan, R.J. and Flaherty, K.T., 2015. New strategies in melanoma: entering the era of
combinatorial therapy. Clinical Cancer Research, 21(11), pp.2424-2435.
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