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VOLUME 2   ISSUE 9   SEPTEMBER 2014   Regional medical practice of concomitant medication CDSCO - REGULATORY MATTERS 1. CONSIDERATION OF ETHNICITY FOR APPROVAL OF NEW DRUGS  Severity distribution of eligible subjects.  Similarity of dose and dosage regimen. Based on the recommendation of the expert committee constituted by the MINISTRY OF HEALTH AND FAMILY  Clinical end-point has to be acceptable to the region WELFARE, it was decided that the following properties of in assessing efficacy. a compound which would make it more likely to be sensitive to ethnic factors shall be taken into 2. PENALTIES FOR SPURIOUS OR consideration during evaluation of new drug SUBSTANDARD QUALITY DRUGS The penalty for manufacture of spurious or adulterated  Non-linear pharmacokinetics. drugs has been enhanced to an imprisonment for a term  A steep dose-response curve (a small change in dose which shall not be less than 10 years, but which may results in a large change in effect) for both efficacy extend to imprisonment for life and shall also be liable to and safety in the range of the recommended dosage fine which shall not be less than Rs. 10 lakhs or 3 times the and dose regimen. value of the drug confiscated, whichever is more. In certain cases, offences have been made cognizable and  A narrow therapeutic dose range. non-bailable. It also provides a tool of compounding of  Highly metabolized, especially through a single offences for dealing with certain minor offences. pathway, thereby increasing the potential for drug-drug interaction. The major categorization of not of standard quality drugs could be:  Metabolism of enzymes known to show genetic CATEGORY A—SPURIOUS & ADULTERATED DRUGS  Administration as a prodrug, with the potential for SPURIOUS OR IMITATION DRUG PRODUCTS are drug ethnically variable enzymatic conversion. formulations manufactured concealing the true identity of the product and made to resemble another drug,  High inter-subject variation in bioavailability. especially some popular brand, to deceive the buyer and  Low-bioavailability, thus more susceptible to dietary cash on the popularity of the original product. The absorption effects. product may or may not contain the active ingredients.  High likelihood of use in a setting of multiple co- ADULTERATED DRUGS are those drugs which are found to contain an adulterant/substituted product or contaminated with filth rendering it injurious to health.  High likelihood of inappropriate use, e.g. analgesics and tranquilizers. CATEGORY B—GROSSLY SUB-STANDARD DRUGS It has also been decided that the following factors may Drugs manufactured by licensed manufacturers and be taken into consideration in deciding whether the reported to have defects of serious nature to affect the available data could be ethnically sensitive or insensitive: quality of the drug. Such defects may arise out of gross negligence or non-conformance to GMPs during Definition of the disease and diagnosis of the patient. manufacture. These defects may broadly be as under:  Choice of control group.  Active ingredient contents below 70% for  Method of assessment of safety—similarity of medical thermolabile products and below 5% of permitted practice to the country of origin. limits for thermostable products.  Duration of trial.  Tablets/Capsules failing in disintegration tests wherever prescribed.

VOLUME 2   ISSUE 9   SEPTEMBER 2014   Liquid preparations showing presence of fungus. conduct of clinical trials of new drugs in India should invariably provide the information on (i) assessment of  Parental preparations failing in sterility, risk versus benefit to the patients, (ii) innovation vis-a-vis pyrogen/endotoxin test or undue toxicity. existing therapeutic option and (iii) unmet medical need in the country.  Vaccines failing in potency, sterility, toxicity or moisture content. All the sponsors / CROs / medical institutions and other stakeholders involved in the conduct of clinical trials in  Presence of any adulterant which renders the the country are hereby directed to adhere to the above product injurious to health. requirement of inclusion of the three parameters in their clinical trial applications with immediate effect. CATEGORY C—MINOR DEFECTS Drugs manufactured by the licensed manufacturers US FDA — NEW DRUG APPROVALS   found not of standard quality because of defects arising out of minor variations in quality. Such defects may arise because of inadequate pre-formulation development DULAGLUTIDE is a new long-acting GLP-1 receptor studies, lack of in process controls exercised by the agonist which increases intracellular cAMP in beta cells manufacturer or unsuitable conditions under which drugs leading to glucose-dependent insulin release and also are stored or transported. Examples of some such the decreases glucagon secretion and slows gastric emptying. DULAGLUTIDE is specifically indicated as an adjunct to  Broken or chipped tablets. diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.  Presence of spot, discolouration or uneven coating. Formulation: Solution for SC injection at a recommended  Cracking of emulsions. initiating dose of 0.75 mg once weekly at any time of day, with or without food, to be injected in the abdomen,  Clear liquid preparations showing sedimentation. thigh, or upper arm. The dose may be increased to 1.5 mg once weekly for additional glycemic control. Change in colour of the formulation. Adverse events: Nausea, diarrhea, vomiting, abdominal Slight variation in net content. pain and decreased appetite.  Formulations failing in weight variation. US FDA approval: September 2014.  Formulations failing to respond to the colour test. 5. NALTREXONE AND BUPROPION—FDC  Isolated cases of presences of foreign matter. NALTREXONE is an opioid antagonist and BUPROPION  Labelling error including nomenclature mistake, Rx, is an inhibitor of neuronal reuptake of dopamine and NRx, XRx, Red Line, Schedule H, Caution, Colour, etc. The NALTREXONE+BUPROPION FDC is specifically CLINICAL TRIALS OF NEW DRUGS indicated as an adjunct to a reduced-calorie diet and The clinical trials on new drugs are regulated under the increased physical activity for chronic weight provisions of DRUGS & COSMETICS RULES 1945 as management in adults with an initial body mass index amended form time to time. The detailed requirements (BMI) of 30 kg/m2 or greater (obese) or 27 kg/m2 or and guidelines for undertaking clinical trials are specified greater (overweight) in the presence of at least one under Rule 122DAA, Rule 122DAB, Rule 122DAC, Rule weight-related comorbidity. 122DD, Rule 122E and Schedule Y of the said rules and Formulation: Extended release tablet orally, twice daily other relevant provisions. dosing. The drug should be discontinued if there is no loss It has been decided that all the applications for the of baseline body weight by >5% after 12 weeks.

VOLUME 2   ISSUE 9   SEPTEMBER 2014  Adverse events: Nausea, constipation, headache, EMA (CHMP) approval: September 2014. vomiting, dizziness, insomnia, dry mouth, diarrhea and potential to cause suicidal thoughts and behaviors and 8. SOFOSBUVIR AND LEDIPASVIR—FDC neuropsychiatric reactions. LEDIPASVIR / SOFOSBUVIR is an FDC of two directly US FDA approval: September 2014. acting antivirals. The active metabolite of SOFOSBUVIR is a pangenotypic inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase, while LEDIPASVIR targets the NS5A protein of the virus. NALOXEGOL is a peripherally acting µ-opioid receptor antagonist which decreases the spasmogenic action of It has been approved by Committee for Medicinal opioids on the gastrointestinal tract. It is specifically Products for Human Use (CHMP) for chronic hepatitis C indicated for the treatment of opioid-induced in adults. The benefits of the FDC with or without constipation in adults with chronic non-cancer pain. ribavirin are very high efficacy against genotypes 1, 3 and 4, including patients post-transplant and/or with Formulation: Tablets of 25 mg for once daily compensated cirrhosis. administration in the morning, on an empty stomach at least 1 hour prior to the first meal of the day or 2 hours Formulation: Film coated tablets 400/90 mg, intended after the meal. Consumption of grapefruit or grapefruit for oral administration. juice is to be avoided. Adverse events: Fatigue and headache. Adverse events: Abdominal pain, diarrhea, nausea, flatulence, vomiting and headache. EMA (CHMP) approval: September 2014. US FDA approval: September 2014. 9. DARUNAVIR AND COBICISTAT—FDC DARUNAVIR is an HIV-1 protease inhibitor antiretroviral EMA — NEW DRUG APPROVALS  drug and COBICISTAT is a pharmacokinetic enhancer. This combination provides sustainable virological suppression if given as part of combination with other NINTEDANIB is a tyrosine kinase inhibitor anti-neoplastic antiretroviral medicinal products for treatment of HIV-1 agent blocking vascular endothelial growth factor infection. receptor (VEGFR-1 and 3), platelet derived growth factor receptor (PDGFR- The FDC is approved in combination with other α and ß) and fibroblast growth factor receptor (FGFR-1 and 3) kinase activity, crucial for the antiretroviral drugs for treatment of HIV-1 infection in proliferation and survival of endothelial and perivascular adults aged 18 years or older. cells, eventually inhibiting tumor angiogenesis. Formulation: Film coated tablets 800/150 mg, intended It is indicated in combination with docetaxel for the for oral administration. treatment of adult patients with locally advanced, Adverse events: Diarrhea, nausea, and rash. metastatic or locally recurrent non small cell lung cancer (NSCLC) after first line chemotherapy. EMA (CHMP) approval: September 2014. Formulation: Soft capsules of 100 and 150 mg, intended for oral administration. Adverse events: Neutropenia (including febrile neutropenia), decreased appetite, electrolyte imbalance, peripheral neuropathy, bleeding, diarrhea, vomiting, nausea, mucositis (including stomatitis), rash and increase in alanine aminotransferase, aspartase aminotransferase and alkaline phosphatyase.

Source: http://kimsbangalore.edu.in/documents/2014/Newsletter-Vol-2-Issue-9.pdf