Hypertension: Developing Fixed-Dose Combination Drugs for Treatment
2017-1001
2018-03-28 2018-01-26 2018-03-28
FDA-2017-D-6878-0004 FDA-2017-D-6878-0003 FDA-2017-D-6878-0005
04:00:00 05:00:00 04:00:00
https://api.regulations.gov/v4/comments/FDA-2017-D-6878-0004 https://api.regulations.gov/v4/comments/FDA-2017-D-6878-0003 https://api.regulations.gov/v4/comments/FDA-2017-D-6878-0005
Anonymous Anonymous Anonymous
Anonymous Anonymous Anonymous
Hypertension: Developing Fixed-Dose Combination Drugs for Treatmentit is very true, majority of hypertensive patients are on a combination of anti hypertension medication. may be its long time in the coming to have a written document on how to combine HTN medication, especially for primary care providers.A lot of drugs are a combination of at least 2 already, which is a great advance in medicine! I dot think physicians should try any medication, combination or single, and track results, not just leave the patient on a medication indefinitely not knowing whether its working or not.These upcoming new developments in fixed dose combinations should be suggestive, not a regulation however as I would like to beleive that Doctors have enough training and knowledge to make the final decision when it comes to their patients, and not be told but regulatory government companies.Thank You for your consideration, THE FIXED COMBINATION DOSE TREATMENT FOR HYPERTENSION IS IDEAL FOR PATIENTS WHO DO NOT LIKE TO TAKE MULTIPLE DOSES OF MEDICATION. HOWEVER, FOR SEVERAL YEARS NOW INSURANCES, INCLUDING MEDICARE D PLANS, HAVE REFUSED TO PAY FOR COMBINATION MEDICATIONS. PROVIDERS HAD TO SEPARATE THE COMBINED INTO TWO DIFFERENT PRESCRIPTIONS IN ORDER FOR PATIENTS TO AFFORD THE TREATMENT. THANK YOU.BILLIE JANICE GRANTHAM-NAPIER, DNP, FNP-CDOCTOR OF NURSING PRACTICE, FAMILY NURSE PRACTITIONER We congratulate the Agency on this guidance and believe it outlines several important clarifications and improved pathways. The rationale for better blood pressure control and better blood pressure combinations is well made.We would like to offer three points of discussion:1.We support the statement The FDA encourages sponsors to market dose combinations that represent clinically meaningful titration steps, but would like to make some related points on this matter:-It would be helpful to quantify this requirement - perhaps at least a 3.0/1.5 mmHg difference between titration steps.-We see a risk of a double standard being introduced, as the proposed standards for titration steps for combination therapy have not been applied to monotherapy, and the vast majority of up-titration steps within monotherapy regimens confer blood pressure (BP) reductions of 3.0/1.5 mmHg.1 Since presumably it is not feasible to revise monotherapy labels, we suggest it would be appropriate to add information to the labelling of dual combinations on the effects of up-titration of the monotherapy components within the combination, by way comparison. For example, for a combination of AB the effects of titration across dose versions of AB would be reported alongside previous evidence on the effects of dose titration for drug A and drug B separately.  -We see the potential that clinically meaningful could be misinterpreted as clinically identifiable. Consideration should be given in the labelling to note that the signal-to-noise ratio for BP measurements means that on an individual basis it is practically impossible to reliably determine the size of the blood pressure change from any individual dose titration step. We suggest that in clinical practice, drops in BP in the weeks and months after initiating treatment are often wholly attributed to that treatment or treatment up-titration step, when in fact they are substantially due to the effects of regression to the mean - hence prescribers can easily overestimate the efficacy of initial treatment, or an early up-titration step. But also, sometimes true treatment efficacy can be masked by the play of chance in BP levels at different clinic visits.2.We support the use of the advocated figure Probability of Achieving Systolic Blood Pressure Less Than 140 mmHg and suggest this could be improved with the addition of a time dimension, and plots for SBP 130mmHg as well as 140mmHg. Furthermore, we advocate an additional figure outlining the evolution of treatment effects over time, with placebo-corrected differences from baseline plotted weekly. A major reason for treatment inertia is the belief that the full treatment effect is yet to emerge and that it takes many months for the full pharmacological benefits to be apparent.2 Informative data assessing treatment effect evolution over time from a placebo-controlled setting would therefore be helpful for prescribing clinicians. 3.Finally, we note that the guidance does not anticipate labelling to reflect the benefits of fixed-dose combinations (FDCs) for improving adherence and overcoming treatment inertia, resulting from the many and varied barriers for patients, physicians and payers in following hypertension treatment algorithms. Furthermore, one of the most important benefits appears to be in overcoming barriers to treatment initiation (or re-initiation) and up-titration among people who are undertreated.34 Previous trials have often focused on FDC vs the monocomponents taken as separate pills, in tightly controlled settings in which adherence has been optimized in order to assess equivalence over short periods of time and support a substitution indication - such trials are not informative regarding the role of FDCs in overcoming treatment inertia in real clinical practice. We note the challenges for a regulatory agency in including comparison groups that are usual care i.e. heterogeneous and often suboptimal. And furthermore, we note that in clinical trials the usual care group often receives care that is in fact better than average, which will tend to lead to underestimation of the benefits of FDCs compared to true usual care. We would suggest nonetheless The Agency provide guidance on study design for Sponsors seeking to add an improvement in adherence to the labelling of an FDC.Anthony Rodgers, Abdul Salam, Emily AtkinsThe George Institute of Global HealthUniversity of New South WalesSydneyAustralia1.Law MR, et al. BMJ  2003;326:1427-31.2.Ferrari P, et al. Reasons for not intensifying antihypertensive treatment (RIAT): a primary care antihypertensive intervention study. Journal of hypertension. 2004;22(6):1221-9.3.Webster et al. International journal of cardiology. 2013;170(1):30-5.4.[22 March 2018]. Available from: http://www.acc.org/latest-in-cardiology/articles/2018/03/07/15/53/mon-8am-triumph-low-dose-triple-combination-bp-lowering-pill-acc-2018.