First-level screening excluded CDR reports with indications for diseases that are not rare. Second-level screening required the reviewer to provide the prevalence of the disease before a decision to exclude or include was made. Discrepancy between the two reviewers was resolved through arbitration of a third independent reviewer T. One reviewer G. If prevalence data were not reported in the CDR report, we sought a Canadian published estimate in the literature, if such estimate could not be found, then the prevalence point estimates was informed from the Orphanet report series [ 7 ].
Full data-set is available from the corresponding author upon reasonable request. We thematically explored reasons for a negative reimbursement recommendation i. Insufficient evidence: in cases where the committee found the evidence to be of poor quality with a high degree of statistical uncertainty and methodological limitations.
Usually, in this category, high-quality studies would have been considered, and the drug would have potentially shown statistical significance in possible surrogate outcomes. The accuracy of the extracted data was verified by a second reviewer T. Categorical variables are presented as percentages. Of records retrieved on February 3, , we identified 63 submissions for DRDs. Of these 63 submissions, four were ongoing at the time of the search, and the reimbursement recommendations and clinical report were not available.
Therefore, there was no information available for these DRDs regarding the studies included in the submission, the price, and reimbursement recommendations. Assessment of the number of DRD submissions made to the CADTH CDR revealed two distinct, contrasting periods: the first period was between and , within which the number of submissions was generally between 4 and 5 per year, and ranged from a minimum of 1 submission in to a maximum of 5 submissions in each of the years , , , and ; the second period was between and , which was distinct from the preceding period in that the number of submissions increased, up to 10, 9, and 8 submissions for the years , , and , respectively.
Number of CDR submissions for drugs for rare diseases per year for the period to Numbers above columns indicate the number of submissions. Examination of these data revealed that Pfizer Canada made more DRD submissions than any other pharmaceutical manufacturer a total of six submissions , followed by Genzyme Canada five submissions , and Alexion, Hoffman-La Roche, and Novartis four submissions each.
Of the 63 DRD submissions, approximately half 30 or This suggests that there is a tendency for DRD submissions to target relatively less prevalent rare diseases. Number of CDR submissions for drugs for rare diseases by indicated disease prevalence. Of the 54 Of the 57 Number of CDR submissions for drugs for rare diseases by the number of clinical studies considered in each submission.
Type of best evidence included in the CDR submissions of drugs for rare diseases. Submissions that do not require clinical review e. The Atlantic Expert Advisory Committee AEAC is an independent advisory group composed of physicians, pharmacists and other persons with expertise in drug therapy and drug use evaluation. The committee makes recommendations to the Atlantic Ministers of Health or delegate regarding the listing of drugs on the Atlantic provincial drug plan formularies.
The approach is evidence-based and the advice reflects the best available medical and scientific knowledge and current clinical practice. Each provincial drug plan makes their own final listing decision based on the AEAC recommendation and jurisdictional factors, such as plan mandates, priorities, and resources.
The manner in which the recommendations are processed is up to each drug plan and listing decisions must be approved by the Minister of Health or delegate.
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Recommended stories. Romania becomes emerging market — Fin. Some groups have lobbied provincial governments to include drugs on formularies made by companies from which they receive grants [ 2 , 3 ]. There has not been any systematic analysis of patient group funding by pharmaceutical companies in Canada and whether there is an association between funding and the activities of groups. Specifically, this research examines whether there is an association between the positions that the groups take about the products under consideration and the receipt of money from companies.
Canada has no national drug formulary and as a result CDR makes recommendations to federal, provincial and territorial drug plans except for Quebec about whether to fund a unique drug-indication combination and pCODR does the same for oncology products. Briefly, CDR and pCODR accept applications from manufacturers and drug plans and then utilize expert panels [ 4 , 5 ] that consider the clinical evidence, plus input from manufacturers, clinicians and patient groups in making their recommendations about whether the plans should list drugs for specific indications.
CDR has been publishing the full submissions from patient groups since April and pCODR has been publishing summaries of submissions since January When patient groups make submissions they are asked to declare any conflicts of interest that they may have and these conflicts need to be stated for their views to be considered by CDR and pCODR. Prior to September , groups making submissions to CDR could ask that their submissions be treated as confidential but in these cases their conflicts were still listed in the CDR Clinical Reports on the drug-indication.
Reports were included if they were labelled complete CDR or a final recommendation had been issued pCODR as of July 22, and if they included a submission from one or more patient groups.
If two or more patient groups collaborated on a submission these were treated as separate submissions from each group if the groups had individual conflict declarations.
Applications from manufacturers where they were requesting a reconsideration of a previous decision were included. From each report the following information was extracted: generic and brand name of drug, indication, company manufacturing the drug, the names of patient groups making submissions, conflict of interest statements from the patient groups, recommendations about funding and whether the recommendation was issued by CDR or pCODR.
CDR issues three types of recommendations—list, list with criteria or conditions and do not list. Similarly, pCODR has three types of recommendations—fund, fund conditional on the drug being cost-effective or only for particular groups of patients and do not fund. Only conflicts with either pharmaceutical companies or lobby groups representing pharmaceutical companies were recorded.
Conflicts could be with the company marketing the drug under consideration or with other companies. Prior to August 31, , CDR did not require groups to say when conflicts had occurred. From September 1 onward, CDR and pCODR aligned their requirements for declaring conflicts, and groups were asked to list only conflicts with companies or organizations within the previous 2 years that may have a direct or indirect interest in the drug under review.
The number of individual drug-indication reports from CDR and pCODR were totaled along with the number of individual patient group submissions per drug-indication, whether the group did and did not have a conflict with the company marketing the drug or have any conflict at all, the total number of conflicts with drug companies for each individual submission and the total number of different submissions from each individual patient group.
The reports from CDR include the full patient group submission, although prior to August 31, CDR gave patient groups the option of refusing to publicly disclose their submissions, but in this situation it summarized patient group views in its Clinical Reports. If the submissions were public, extracts were taken from the submission. If more than one patient group made a submission about a drug-indication each submission was treated separately.
If the full submissions were confidential, the CDR summaries were used. However, this was only possible if there was only a single submission since the CDR summaries did not attribute views to a particular group. Similar to the situation where CDR summarized confidential group submissions, if there was only a submission from a single patient group to pCODR then extracts from the summaries were used.
Disagreements were resolved by discussion. Patient groups were put into three categories—those with a conflict with the company marketing the drug, those without a conflict with the particular company but with conflicts with other companies and those with no conflicts at all. The distribution of views positive, neutral, negative of these three categories of patient groups were compared. Views from patient groups were dichotomized as positive or negative with a neutral view first being treated as positive and then as negative.
These comparisons were done for all drug-indication recommendations except those for subsequent entry biologics SEB and separately for subsequent entry biologics.
A SEB is a product that is similar to, and would enter the market subsequent to, an approved innovator biologic [ 8 ]. This group of drugs was chosen because patient groups may have been funded by companies marketing the originator biologic or the SEB and the source of the funding may have affected the view of the group. Besides a final report, pCODR also issues preliminary reports with a funding recommendation.
Patient groups are offered the opportunity to comment on those recommendations and give reasons for their comments. Comments are one of three types—agree, agree in part and disagree. If a patient group made a comment and reported the presence or absence of a conflict the comment was recorded along with the reasons that they gave to justify their comments. The distribution of the type of comment was compared for each of the three possible funding recommendations.
Washington, D. If you make a reporting mistake, you must amend your Form U. The Authorized Official or the Agent will need to unlock the submission to make the changes. There will be an opportunity to explain why the change is being made - please be sure to complete that section. Additionally, you will need to file a self-disclosure form. Note that if you did not claim and substantiate if required a particular data element as confidential at the time you submitted the data element to EPA, you cannot later add a claim of confidentiality.
A submitter would also be expected to review other information which the manufacturer including importer may have in its possession. This standard requires that submitters conduct a reasonable inquiry within the full scope of their organization not just the information known to managerial or supervisory employees.
The inquiry would be as extensive as a reasonable person, similarly situated, might be expected to perform within the organization. The standard does not necessarily require that the manufacturer conduct an exhaustive survey of all employees.
Note, however, that if particular information cannot be derived or reasonably estimated without conducting further customer surveys i. Thus, there is not a need to conduct new customer surveys for purposes of the CDR. Submitters must report the highest-level parent company located in the United States and, if one exists, the highest-level foreign-based parent company 40 CFR See the Instructions for Reporting for examples of how to identify the parent company ies in different situations on the CDR website at www.
Reporting should be based on ownership of the manufacturing entity, as of the date that the report is submitted. EPA acknowledges that there will be submitters who have been involved in an acquisition or divestiture since the last submission period and for whom certain information is not known or reasonably ascertainable.
If information is not known or reasonably ascertainable, it need not be reported under the CDR. Because all of the assets and liabilities of Company X were merged into Company Y, and Company Y continued as a going concern, Company Y is required to report the entire 70, pounds of the chemical substance manufactured at the site during the reporting year e. By the time of the CDR submission in , Company B owns the entity that conducted the manufacturing in Company B should report its own identity, not the identity of a previous owner.
More information about the effect of the sale of a company on reporting requirements can be found in the Reporting After Changes to Company Ownership or Legal Identity fact sheet on the CDR website. Assuming each of the facilities met or exceeded the production volume threshold for the subject chemical substance during any calendar year since the last reporting period, the company should submit a Form U for each of the closed facilities and report the CDR information to the extent that it is known to or reasonably ascertainable by the company.
Participants in the joint venture may determine among themselves who will report. If no report is submitted when required, EPA may hold each party in the joint venture liable for the failure to report. By the time of the CDR submission in , Company XYZ is the current name of the business entity that conducted the manufacturing in Company XYZ should report its current name, not a prior name that it used when manufacturing in The company should list the site that controls the import transaction, which may or may not be the site that receives the material.
The site where a chemical substance is imported is the site of the operating unit within the organization that is directly responsible for importing the substance and controls the import transaction. See the definition of site in 40 CFR If for a given substance that a company imports at a given site, more than one person meets the definition of importer at 40 CFR See 40 CFR The definition does not require different companies located at the same site to report together.
However, if a single company operates multiple plants at a single site, those plants should report together for the site. See the definition of site at 40 CFR Site A was not the site directly responsible for the import of this chemical substance.
The import of the chemical should be reported by Site B. The NAICS code is the standard used by Federal statistical agencies in classifying business establishments for the purpose of collecting, analyzing, and publishing statistical data related to the U.
Census website at www. In those circumstances, you may report up to three NAICS codes to more appropriately describe your site. For example, headquarter sites that import for other sites may have difficulty identifying a single NAICS code. It is the authoritative resource for basic information about chemicals, biological organisms, and other chemical substances of interest to EPA and its state and tribal partners.
However, submitters of Inventory-listed substances should generally know already what CASRNs have been assigned to their substances. The use of the SRS to obtain the identities for all CDR reportable chemical substances is a convenient way to meet the chemical nomenclature requirement and will help to prevent errors in the reporting of chemical identification information for the CDR.
If the PMN case number of a confidential substance was used for reporting in the past, submitters can use the PMN case number to search the SRS to populate the pertinent chemical identification information for the confidential chemical substance listed on the TSCA Inventory.
Submitters can use the SRS to select the correct Accession Number corresponding to the confidential chemical substance intended to be reported the generic name corresponding to the Accession Number will automatically be incorporated into the report.
EPA recognizes that there are certain circumstances where a submitter occasionally may not be sure of the particular PMN case number and Accession Number that EPA has assigned to one of its confidential chemical substances so that they do not have enough information to search the SRS.
This could happen, for example, if the chemical substance were originally reported as part of a consolidated PMN and a submitter did not learn from EPA which particular case number in the consolidated PMN number sequence corresponds to which of the several reported confidential chemical substances.
The Agency will respond to such inquiries in as timely a manner as possible. It is the responsibility of the submitter to contact the Agency for such information in sufficient time to allow for the Agency to respond. If an importer submitting a report cannot provide the information specified in 40 CFR Contact information for the supplier, a trade name or other designation for the chemical substance or mixture, and a copy of the request to the supplier must be included with the importer's submission for the chemical substance.where applicable, the CDR within 30 days; failure to respond twice within an EHR reporting period would result in that EP not meeting the measure. Active Engagement Option 3 – Production: The EP has completed testing and validation of the electronic submission and is electronically submitting production data to the PHA or CDR.