The FDA conducts a preliminary review of an NDA within 60 days of its receipt and informs the sponsor whether the application is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA has agreed to specified performance goals in the review process of NDAs. Most such applications are meant to be reviewed within ten months from the date of filing, and most applications for "priority review" products are meant to be reviewed within six months of filing. The review process may be extended by the FDA for three additional months to consider new information or clarification provided by the applicant to address an outstanding deficiency identified by the FDA following the original submission.

1. P. Johnson, “Quality In, Quality Out:Regulatory Drivers of Supplier Quality Management in the Pharm and Biopharma Industries,” Xtalks Webcast (September 18, 2018). 2. FDA, “Valsartan Products Under Recall,” fda.gov, August 28, 2018. 3. P. Magee and J. Barnes, “British Journal of Cancer , 10 (1) 114-122 (1956), 4. C. Purdy, “A Common Blood Pressure Medicine is Being Recalled Because it Was Mixed With NDMA". 5. A. Tricker et al, Carcinogenesis 12(2); 257-261 (1991). 6. M. Jagerstad, Mutation Research 574(1-2), 156-172 (August 2005) 7. EMA, “Valsartan: Review of Impurities Extended to Other Sartan Medicines,” Press Release, September 21, 2018. 8. FDA, “FDA Announces Preliminary GC/MS Headspace Method for Determining NDMA in valsartan” Press Release, August, 2018. 9. EDQM, “OMCLs Release Three Methods for Determination of NDMA in Sartans,” Press Release, September 21, 2018. 10. FDA Press Release, “FDA Places Zhejiang-Huahai on Import Alert,” fda.gov , September 28, 2018. 11. EMA, Press Release, “EU Inspection Finds Zhejiang Huahai Site Non-Compliant,” ema.europa.eu , September 28, 2018. 12. FDA, Form 483, fda.gov

We manage our business through a small number of senior executive officers. We depend on them even more than similarly- situated companies.

All three NOS isoforms are expressed in bone and the role of NO in bone metabolism has been confirmed in intact animals with single-gene deletion of NOS isoforms53. However, which subtype of the affected NOS helps to regulate pro-inflammation (Fig. 3) and bone formation (Fig. 4) of BMSCs stimulated by the positively-charged surface (PArN) is unknown. Herein, the effects of the three isoforms on osteo-genetic expression in the presence and absence of NOS inhibition is studied in order to disclose the signaling pathway of NO. Recent studies54 indicate that targeted deletion of the eNOS isoform in mice leads to an osteoblast-driven mild osteoporotic bone phenotype. As shown in Fig. 6a, the same tendency is observed from the blank and PArN groups. Stem cells exposed to L-NAME increase the mRNA expression of Runx-2 but significantly reduce the ALP expression. Therefore, inhibition of eNOS has little effects on the OCN and BSP expressions in BMSCs cultured on PArN. When the nNOS inhibitor (Sper) is added to the cell culture medium instead of L-NAME, the nNOS expression is also suppressed on both the blank and PArN (Fig. 6b). These results are partially evidenced by those obtained from mice with global deletion of nNOS55, showing increased bone mass due to a reduced bone turnover rate and a phenotype that is repeated in mice with deletion of all three NOS genes. The same change observed from the blank and PArN indicates that nNOS is not the signal pathway for the positively-charged surface with tertiary amines (PArN) concerning regulation of the BMSCs osteogenic expression.

The Anti- Kickback Statute makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf) to knowingly and willfully solicit, receive, offer, or pay any remuneration that is intended to induce the referral of business, including the purchase, order, or prescription of a particular drug, for which payment may be made under a federal healthcare program, such as Medicare or Medicaid.

yes you are correct Paul, i just used lactic acid as an example. I should have used the homocysteine/b12 deficiency instead, which is in fact a real issue.

However, regulators must now grapple with the question of how members of a class of potent probable carcinogens wound up in the pharmaceutical supply chain in the first place.  NDMA, widely used in cancer research, was the poison of choice in two sensational murders in the U.S. and Germany (7) in 1978, while growing evidence of its impact and that of other nitrosamines helped drive public area smoking bans and intensive process changes in the food industry.  

Upon exercise of the OWL License Agreement Option, we will own all rights, title and interest in and to (i) the complimentary diagnostic tool for NASH using Aramchol, excluding serum and plasma markers developed by OWL using proprietary methods and any of the OWL patents, OWL’s know-how, and any other results of whatsoever nature, which are discovered, developed or invented in the course of, or directly arising from, the performance of the Research, excluding our technology, or the Research Results, which is owned by OWL; (ii) the complimentary diagnostic tool for NASH using Aramchol intellectual property; (iii) all results and intellectual property pertaining to (a) our technology, (b) markers or other diagnostics for use in connection with liver diseases and/or cholesterol gallstones and/or any other indications utilizing Aramchol and any future synthetic fatty-acid/bile conjugates or FABACs owned by us, (c) metabolomics markers predicting therapeutics or safety response of Aramchol; or (iv) any additional markers improving NASH patient selection for treatment with Aramchol that are generated, discovered, reduced to practice and/or arising in the course of and/or from the performance of any research, services and/or development activities by or on behalf of or for us (including by OWL hereunder), excluding research results, and including any regulatory filing or approval (if any) filed or obtained by us or any of our affiliates in respect of the OWLiverGAL kit and any other product, kit, device, material, process, method, activities or service that incorporates, uses, or is reliant upon the licensed technology, or the Licensed Technology Product, and all communications with regulatory authorities, and any data, information or document covered by data protection or data exclusivity, production processes, standard operating procedures, subcontractors’ information and other technical information required for the sale and/or commercialization of the Licensed Technology Products, test protocols and final reports of any testing or studies with respect to the Licensed Technology Products.

Lipoprotein-deficient serum (LPDS) was prepared following the protocol of Renaud et al.31 with slight variation. Briefly, FBS was adjusted to a density of 1.215 g/mL by adding KBr. After overlaying the FBS with a KBr solution at the same density, the mixture was centrifuged for 65 h at 235,500 g at 4 °C. The floating lipoproteins were removed and the remaining serum was dialysed against 6 changes of 4L Phosphate-buffer saline (PBS) pH 7.4 at 4 °C.

        Efforts to educate the medical community and third-party payors on the benefits of our product candidates may require significant resources, including management time and financial resources, and may not be successful. If any of our product candidates is approved but does not achieve an adequate level of market acceptance, we may not generate significant revenues and we may not become profitable. The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on a number of factors, including:

        We are currently developing zilucoplan for subcutanous, or SC, self-administration. Unsatisfactory drug availability due to problems relating to this route of administration or the ability of the drug to bind to its target is another potential cause of lack of efficacy of zilucoplan if and when it is commercialized. C5, the target of zilucoplan is predominantly found in blood. For gMG and PNH,

        The pre-specified primary efficacy endpoint was the change in QMG score, a physician-administered assessment of MG-related muscle weakness, from baseline to week 12. The key secondary efficacy endpoint was the change in MG Activities of Daily Living, or MG-ADL, score, a patient-reported outcome measure, from baseline to week 12. Significance testing was pre-specified at a 1-sided alpha of 0.1.